Magdalena Zernicka-Goetz: The Dance of Life: Symmetry, Cells and How We Become Human. Book review.

The Dance of Life

Magdalena Zernicka-Goetz, Roger Highfield (2020) The Dance of Life. Symmetry, Cells and How We Become Human.

Magdalena Zernicka-Goetz is a Polish-British developmental biologist and experimental embryologist. "I am one of the relatively small number of scientists who have cultured human embryos, allowing them to grow and thrive, although most of my work has been with mouse embryos (...) But I have to admit that I was also driven by the oldest scientific motive of all: I wanted to gain fundamental understanding of a critical chapter in the story of a human life, as this is when the embryo starts to grow and the overall body plan starts to be decided."

Roger Ronald Highfield is an author, science journalist, broadcaster and Science Director at the Science Museum Group.

Magdalena Zernicka-Goetz

This is an interesting and important book about ground-breaking discoveries of the development of the human embryo and also because of how her scientific research unexpectedly has been intertwined with her personal life:

"Magdalena Zernicka-Goetz was pregnant at 42 when a routine genetic test came back with that dreaded word: abnormal. A quarter of sampled cells contained abnormalities and she was warned her baby had an increased risk of being miscarried or born with birth defects. Six months later she gave birth to a healthy baby boy and her research on mice embryos went on to prove that – as she had suspected – the embryo has an amazing and previously unknown ability to correct abnormal cells at an early stage of its development." (from the publisher)

It appeared that her prenatal test of her pregnancy showed a trisomy 2: three copies of chromosome 2 (one extra copy) in a quarter of the tested cells. This is a very rare but serious chromosome abnormality [1]. 

normal human chromosomes (♂) wikipedia

The most frequent trisomies are 13, 18 and 21, and they are the only ones compatible with life birth. This is because these three chromosomes are small and have few protein-coding genes: chromosome 13 has 327, chromosome 18 has 270,and chromosome 21 has 234 protein-coding genes. Of those three, trisomy-21 is most frequent, this chromosome happens to have the smallest number of protein-coding genes. However, chromosome 2 is the second-largest human chromosome with 1309 protein-coding genes. A trisomy-2 in all cells is not compatible with life. The fact that later she had a healthy baby is surprising at first sight. However, the test was a CVS (Chorionic Villus Sampling)  performed between 10 and 13 weeks gestation. CVS is a sample of tissue from the placenta. It appeared that there was a mosaicism. Later in her pregnancy she had a second test, an amniocentesis (usually between 16 - 20 weeks) which had a normal result. So, she did not really take a huge risk by continuing the pregnancy [1]. Obviously, this was a very emotional and stressful period in her life. These personal details add greatly to the value of the book. So, it is not 'just' a book about her scientific discoveries. These personal details matter, because after getting the CVS result, she switched her lab research activities immediately to the question whether an embryo was able to get rid of abnormal cells ('self-repair').

Although I am familiar with chromosomes, prenatal and postnatal chromosome analysis, I was unfamiliar with the in vitro culture of human and mouse embryos and learned a lot of new interesting facts. She consequently refers to 'self-repair' of the embryo with abnormal chromosomes. I am inclined to interpret the disappearance of abnormal cells in an embryo as a case of the dying of chromosomal abnormal cells. Anyway the hypothetical 'self-repair' fails in the case of trisomy-13, 18 and 21 and all other chromosomal abnormalities (too many to list them here!). Trisomy occurs in a relatively high frequency of 1 in every 700 babies born. So, in these cases 'self-repair' fails. Furthermore, "Around 30 percent of early pregnancies fail before the embryo implants in the body of the mother, with another 30 percent around that time". And then there are hundreds of other birth 'defects' such as Conjoined twins, Cleft Lip, etc. A problem for both 'self-repair/dying of cells' interpretations is to explain the fact that trisomy-2 placental cells were able to grow to a rather large percentage of 25% despite this serious abnormality.

'Self-organizing' human embryos

"To illustrate just how remarkable your origins are, and the extra-ordinary process of embryo self-organization, let's imagine building a house in the same way as your body built itself. First of all, there would be no plans, as such, to construct your body. Nor would there be a blueprint or an architectural drawing or design. There are instructions, but if they work in the same way as the twenty thousand genes used to build your body, there would be no simple relationship between these instructions and how the final house appears, just as there is no simple relationship between a recipe and the appearance of a cake. There is no project manager ... Because this house self-organizes ..." (from the Introduction) [3].

Ethics

Should human embryos be used in research?

 

Chapter 7 is the first chapter in which Magdalena Zernicka-Goetz discusses ethics of experimenting with human embryos. "Although an early embryo is not a person, I believe that it deserves protection." She extends this respect to mouse embryos:

"In my lab, everyone is taught to show the early mouse embryo respect. I have a rule that ad hoc meetings, seminars, coffee breaks, and other distractions have to wait until an experiment using a mouse embryo is finished and the embryo has been safely returned to the incubator to continue its development, as it would in the body of the mother. Woe betide anyone in my laboratory who does not treat life with respect." (Chapter 7 Should human embryos be used in research?)

This is the first and only instance she discusses the ethics of mouse embryos [2]. Chapter 7 is exclusively about the ethics of culturing human embryos (page 588/1273 of my eBook). Magdalena Zernicka-Goetz has worked for three decades with mouse embryos and created hundreds of mouse embryos just for one project. So, the total number must be in the thousands. I could not find how mouse embryos are created. The obvious source is mouse mothers. She mentions 'foster mothers' and 'foster mouse mothers'. Despite the claimed respect for mouse embryos, respect for the adult mouse, the mothers of the embryos, seems to be totally absent:

"Because, of course, we could not test my hypothesis on human embryos, we tested it on mouse embryos." (chapter 8)

Adult mice are exempt from moral considerations. You just use them in unlimited quantities. In contrast to an embryo of a few weeks, adult mice feel pain and stress.

Conclusion

I highly recommend this book. If you are not interested in welfare of lab animals the book is very enjoyable and brings you up to date in the field of developmental biology and artificial embryos. However, if you care about the welfare of lab animals, her complete lack of interest in animal welfare is disturbing. Unfortunately, Magdalena Zernicka-Goetz is no exception. The majority of experimental biologists do animal experiments.

 

Appendix

Scientific and ethical arguments against animal experiments illustrated with quotes from her book:

• "we needed to study not only mouse but also human embryos because they do not develop in quite the same way from the time of implantation." (Chapter 6)
  
•  "Surprisingly, human and mouse embryo architectures diverge widely at this point" (Chapter 6)
• ""although human and mouse blastocysts appear similar at first, their architectures look dramatically different after a few days." (Chapter 6)
• "while we can get valuable insights by carrying out research on other mammals, only by studying human embryos will we be able to understand human development." (chapter 6)
• "Different species of mammal have adopted different strategies to implant in the uterus ..." (Chapter 6)
  
• "Given the important differences in development between the mouse and the human..." (Chapter 7)
• "we start to understand why the development of mice and humans is so different, even though they share virtually the same set of genes." (Chapter 9)
• "The atlas indicates that some organs in humans develop much earlier than in chick or mouse embryos and some later, yet another warning that it is not straightforward to extrapolate from the findings of animal research, say, the effect of toxins on development." (Chapter 10) 
• "We now know that this can happen in the mouse embryo, but we still don't know for sure whether this might occur in a human embryo." (Chapter 10, 76/138)
• 'this emphasizes the value of the mouse embryo as a model system and, at the same time, the need for studies of human development." (Chapter 10).

Further Reading

• Zernicka-Goetz lab home page features the most important and ground-breaking publications ('synthetic' embryos). A synthetic embryo is an embryo which is generated from different stem cells, not generated by the fusion of egg and sperm (chapter 9) and can be made in large numbers. Interesting aspect is the factors that cause self-assembly of a synthetic embryo (see: Philip Ball How Life Works).
• Gretchen Vogel (2016) Pushing the limit. By culturing human embryos for longer than ever, Magdalena Zernicka-Goetz is revealing their “powerful beauty”—and sparking debate. Science, 28 Oct 2016 (recommended!).
• video: The Dance of Life: How Do We Become Ourselves? - Magdalena Zernicka-Goetz (youtube).
  
• EPA scraps plan to end mammal testing by 2035 Science 19 jan 2024.

"New technologies are useful as a supplement to animal experiments, Sass says, “but I’m not sure that they’ll ever be able to tell us whether a child exposed to lead as a fetus is going to have trouble sitting still in a classroom.”

 Nederlands:

• Prof. Kees Brunia over vivisectie: Onze weg naar de kennis van het centrale zenuwstelsel is bezaaid met dode kikkers. blog 17 maart 2015
  
• Duizenden muizen voor niets opgeofferd voor de medische wetenschap? blog 9 april 2013
• De meeste medische experimenten met chimpansees waren overbodig blog 5 nov 2012
   

Update 24 Apr 24

The Dutch government invests in animal-free innovations 

Kabinet investeert in proefdiervrije innovaties

"Het Nationaal Groeifonds investeert 124,5 miljoen euro in een nieuw Centrum voor Proefdiervrije Biomedische Translatie. Van deze investering wordt 55 miljoen euro direct en 69,5 miljoen euro onder voorwaarden toegekend. Het doel van het centrum is om veiligere, effectievere en betere medische behandelingen te stimuleren en tegelijkertijd dierenleed te verminderen. ... 

Tegelijk blijkt steeds vaker dat de resultaten verkregen uit dierproeven maar beperkt of zelfs helemaal niet vertaald kunnen worden naar de mens. In de meeste van deze biomedische ontwikkelingstrajecten blijkt pas tijdens de studie met patiënten dat dierproeven niet de therapeutische werking in de mens voorspellen."

Most remarkable:

it’s becoming increasingly clear that the results obtained from animal experiments can be limited and ineffective. In most biomedical development pathways, it is only during in-human studies that it becomes apparent that the animal experiments conducted were unable to predict therapeutic effects in humans. " !

Update 26 Apr 24

Mariana Lenharo (2024) Do insects have an inner life? Animal consciousness needs a rethink. Nature 19 April 2024.

A declaration signed by dozens of scientists says there is ‘a realistic possibility’ for elements of consciousness in reptiles, insects and molluscs.

Crows, chimps and elephants: these and many other birds and mammals behave in ways that suggest they might be conscious. 

Notes

1. Outcome of pregnancies with trisomy 2 cells in chorionic villi   Prenat Diagnosis, 2010. Conclusion: In at least 95% of cases with trisomy 2 in CVS cultures there is confined placental mosaicism (CPM). The prognosis is good, but in about 15% of cases there is fetal growth restriction. On the other hand: "most embryos from women ⩾40 years old are chromosomally abnormal and rarely develop further." from: Egbert R. te Velde , Peter L. Pearson (2002) The variability of female reproductive ageing.
   
2. Ignorance and indifference: "Despite the plethora of scientific evidence for climate change, for instance, many people still avoid engaging with facts about global warming. Nor do they always want to know about the harsh living conditions of farm animals. And consumers often ignore the ethical origins of the products they purchase." Scientific American article Why Some People Choose Not to Know, 11 Dec 2023. 
3. This idea that there is no blueprint of the body in DNA is forcefully argued by Philip Ball (2024) How Life Works. See my previous blogs. Magdalena Zernicka-Goetz uses the word 'self-organization'. This a very general and vague concept. Turing models make 'self-organization' quantitative and testable.

Curieus patroon op vacuümglas na een forse regenbui

regelmatig patroon van cirkels op raam

 

Grote verrassing! En enige ongerustheid. Na het openen van de gordijnen 's ochtends vroeg zie ik condens op het raam met een mysterieus regelmatig patroon van allemaal evengrote cirkels. Nooit eerder gezien. Wat heeft dat te betekenen? Waar komen die cirkels vandaan? 

Het patroon zit over het hele raam. Aan de randen zit het niet. Het blijkt op de buitenkant van het raam te zitten. Het is condens. Het had de vorige dag flink geregend. Kennelijk geeft de combinatie van vacuümglas + hoge luchtvochtigheid buiten + kou buiten = condens. Alleen het patroon is totaal onverwachts. 

Detail: heldere cirkel rond afstandshouder
begrensd door condens.

Bij nader onderzoek blijkt dat de doorzichtige cirkels, waar dus geen condens zit, precies op de plaats zitten van zgn. afstandhouders. De afstandhouders zijn de kleine zwarte puntjes en zijn het middelpunt van de cirkels. Deze afstandhouders zitten er om te voorkomen dat de twee glasplaten tegen elkaar aan klappen door het vacuum. Puur natuurkunde. Ik heb dit verschijnsel nooit ergens gezien of gelezen [1]. Ik heb het daarna niet meer gezien. Zeldzaam dus. Wel condens aan de binnenkant van het raam, maar nooit aan de buitenkant en zeker niet in dit regelmatige patroon. 

In feite is de condens aan de buitenkant een goed teken. Het betekent dat het glas aan de buitenkant koud is en aan de binnenkant warm [2]. Conclusie: isolatie werkt goed. Maar: condens aan de buitenkant betekent dat het raam koud is, dus het ontbreken van condens in die cirkels betekent dat het plaatselijk warmer is. En dat moet betekenen dat daar de warmte van binnen naar buiten lekt via de afstandhouders. Fysiek contact. Helaas kan vacuümglas niet zonder die afstandhouders. Dus die lekkage is onvermijdelijk. Ik weet niet hoeveel warmte er weglekt. Hoe kouder en vochtiger het buiten is, hoe kleiner de cirkels. Als 's ochtends de buitentemperatuur stijgt en de luchtvochtigheid daalt zullen de 'warme' cirkels groter worden totdat alle vocht is verdampt.

Die afstandhouders lijken dus een nadeel, maar bedacht moet worden dat dit glas getest wordt met afstandhouders. Dat kan niet anders. De isolatiewaarde van glas wordt uitgedrukt in een U-waarde. Hoe lager de U-waarde, hoe beter het glas isoleert. De U-waarde van vacuümglas is 0,4 - 0,7 volgens Milieu Centraal. Die waarde is dus noodzakelijkerwijze inclusief de afstandhouders. Dus in theorie zou de U-waarde nog lager kunnen zijn als er minder of helemaal geen afstandhouders nodig zouden zijn! Maar dat gaat dan weer tegen de wetten van de natuurkunde in ...

 

Berekening totale oppervlakte cirkels *)

• Het glas in bovenstaande foto heeft 29 rijen van 21 afstandhouders = 609 afstandhouders in totaal. 
• de afstandhouders zelf zijn plm. 1 mm in diameter, maar de cirkels hebben een diameter van tenminste 2,5 cm
  
• De oppervlakte van een cirkel met 2,5 cm diameter = pi x r2 = 3,14 x 1,25 x 1,25 = 4,90625 cm2. (2,5 cm is de minimum doorsnede)
  
• De totale oppervlakte alle cirkels = 609 x 4,90625 = 2.987,9 cm2.
• Het raam heeft een oppervlakte van 120x162 cm = 19.440 cm2
  
• Het percentage cirkels van totale glasoppervlakte = 15,4 %

dwz 15,4% van het oppervlakte van het raam laat warmte door (op het moment van de meting). Maar er zijn ook cirkels met 3 cm en 4 cm diameter (afhankelijk van het stadium). Dus 15,4% is een minimum. De cirkels verdwijnen vanzelf na 1-2 uur afhankelijk van de zon.

 

*) 18 april: De tekst is aangepast naar aanleiding van een oplettende lezer.  Duidelijk is gemaakt dat de afstandhouders zelf maar plm. 1 mm dik zijn en het woord 'doorsnede' is vervangen door 'diameter'.

NB: een aardig filmpje dat uitlegt wat vacuümglas is en welke soorten er zijn.

Noten

1. Iemand tipte mij dit filmpje waar op dit tijdstip precies hetzelfde patroon te zien is! [16 april]
   
2. Ik heb de oppervlakte temperatuur aan de binnenkant van het raam laten meten met een 'warmtepistool': 20 graden! [15 april 2024]
   

Rolie Barth replies to his critics: What have pufferfishes and plasmas in common?

pufferfish (Tetraodon mbu) (wikipedia)

In this blog I will give some more clarification about my previous blog Circular causality, another secret of life?, particularly to some remarks of Gert Korthof, which I repeat in my own words.

Gerts question is this: are all components of the systems (molecules, cells, regulatory networks) that self-organize into patterns or structures not gene products? ‘All physical processes you point out are not in 'a glass of water' or any artificial laboratory environment, no, always in a cell or an organism.’

Comparing the skin of a giant pufferfish (Tetraodon mbu) and the patterns of plasmas (a glow discharge) reveals that the skin pattern as well as other biological patterns are physical of nature. The resemblance demonstrates that mutations of genes and natural selection did not make the pattern, but selected it from physical possibilities.

First, let’s start with the pufferfish [1], what a beautiful skin pattern! (see picture above). Is this a unique biological phenomena? To answer this question we turn to plasma physics, a research field in which I have worked for more than 30 years  at the FOM Instituut voor Plasmafysica. My job was to measure the temperature of the plasma electrons. In most experiments particles in plasmas are not evenly distributed but many kind of patterns can appear.
Plasma physicists of the Working Group Purwins (University of Münster, Germany) have built devices to generate low temperature plasmas [2]. A plasma is an ionized gas with free moving ions and electrons which are able to conduct electrical current. Making such plasma between two parallel plates (electrodes) the physicists found all kind of patterns. The patterns show up at the two plates due to the plasma-surface interaction and are made visible using one transparent electrode. A digital camera is applied to record the images. The optical pattern corresponds to the current density pattern in the plasma.

At certain values of the AC voltage a pattern was found that is quite similar to that of a pufferfish. In the figure below tree patterns are shown: left – a pufferfish skin [1], middle – a pattern of the plasma surface interaction [2] and right – a simulation using the Gray-Scott model [3].
Comparing a part of the pufferfish skin (left) and a pattern of the plasma surface interaction show a remarkable resemblance. Indeed, they are not identical but a great similarity cannot be denied.

The third image (right panel) shows the result of simulations using some kind of Turing model, the so called Gray-Scott model. All these modeled processes belong to the large family of reaction diffusion processes for two ore more species of particles, which can be: electrons, ions, chemicals, morphogens, cells and also larger entities. Analyzing these reaction diffusion processes can partly be done analytical, but to determine patterns requires computer simulations.

So, what have pufferfishes and plasmas in common? In both cases reaction diffusion processes created similar patterns that correspond more or less to mathematical simulations of these phenomena. It is obvious that the patterns produced by the interaction of the plasma with the transparent plate (electrode) are the result of physical laws of nature without the need of any external information (like genes in the biological situation). This demonstrates that biological patterns like that of the pufferfish were not invented but discovered by evolutionary processes. These patterns result from physical mechanisms. Of course, in the biological pattern formation genes play important roles:
1. Most morphogens are proteins, build by genetic information.
2. Feedback loops of these systems consist of genetic networks and physical mechanisms, like diffusion.
3. Genes save information about how to reuse the physical process during next generations.
4. Contrary to purely physical processes, the biological variant of these processes can be modified by gene mutations or even by epigenetic processes.

Finally, the resemblance of pufferfish and plasma patterns also show some important features of the position information model of Lewis Wolpert, described by Marleen in reply to my previous blog. She wrote: “The patterning is well described, but can also be described by a simple gradient of morphogens that have to pass a threshold value”, where (in my own words) every threshold is genetically coded. This model is suitable to understand the creation of rather simple, linear patterns like the segments of insects, the swivels of backbones, tails of dino’s and the like. But simulating a pufferfish pattern with this model would require a lot more genetic information than describing it by a Turing model. The model of Wolpert requires two genetically coded threshold values for each stripe … In the Turing model the number of stripes and their separation distance is a matter of tuning two of the system parameters and not of adding new parameters.

In conclusion: the fact that the pufferfish skin pattern and plasma patterns show such close similarities clearly demonstrates that these patterns are generated by physical mechanisms. Of course, genes are not unimportant because they produce the morphogens and are part of the feedback loops necessary for the pattern generating processes. Under these patters lie the physical rules and mechanisms for the complex interaction of a large number of particles. Generally spoken, these patterns are formed by the collective behavior of interacting particles which are part of non-linear dynamical systems, like physical plasmas and biological tissue.

 

References

1. Pufferfish image: Wikipedia
2. Plasm pattern and plasma experimental setup: Juan Pablo Trelles, ‘Pattern formation and self-organization in plasmas interacting with surfaces’, 2016, J. Phys. D: Appl. Phys. 49, 393002, Figure 3. See also: H. -G. Purwins, 2011, IEEE Trans. Plasma Sci. 39-11, 2112.  
3. Simulated pattern: simulation for a Gray-Scott model, k = 0.61 and F = 0.42. Take look at this website with a extended simulator of such patterns: https://www.mrob.com/pub/comp/xmorphia/index.html.
    

hier nog een geweldige foto van de pufferfish !

Circular causality, another secret of life – on the occasion of Philip Ball's How Life Works

 

 guest blog post by Rolie Barth

 

Philip Ball has published an impressive study searching for the most important processes controlling the long way from genes and cells to genetic networks, tissues, organs and bodies. This implies he is talking about eukaryotic cells and their development and evolution. I start this blog with a short summary of the general picture he presents in his book. Then I discuss the concept of circular causality in more detail using a diagram to explain the multilayered nature of developmental processes. Finally, I will give an example of such a process.

If I understand Ball correctly, he is arguing for a view of life in which – in my own words – circular causality plays the leading role. Unfortunately, he himself did not mention this concept explicitly. But anyway, he frequently writes about top-down and bottom-up causality between the different layers of organization in an organism.
Genes play an important role in a multitude of complex processes, characterized not only by linear causality (from bottom to top, from genes to tissue) but also by feedback loops between the different levels of life: genes, networks, cells, tissues, bodies and groups of organisms in ecological systems. All these levels of organization are complex systems that are mainly characterized by (my words) the laws of biophysical phenomena whose dynamical behavior can be understood using the chaos theory. Even though Ball does not mention this theory (well, he does mention the catastrophe theory once), he often uses terminology from chaos theory, in particular: attractors. He describes attractors as valleys or basins in a landscape of possibilities. They are called attractors because the final state of a dynamical system is, as it were, drawn to one of those valleys (one of the possible final states).
To be honest, I might not have recognized this all-round scheme if I had not written about it in part II of my book De kosmos en het leven, een Meesterwerk, 2021 (The Cosmos and Life, a Masterpiece). 

Thinking about complex processes from the perspective of circular causality, the question of what is the most important part of the system actually becomes irrelevant. If we want to find an organizing center, I would talk about cell-centered life.
Considering the importance of the concept of circular causality one could speak about the third secret of life next to the DNA-code (first) and allostery (second, according to Jacques Monod). 

 

What is circular causality?

Many, many biological processes, as well as physical processes, are characterized by feedback loops between parts of a system. To clarify my point, think of the temperature control system of your home heating system. The room temperature is measured and when it is lower than the desired temperature the control unit sends a signal to the boiler to start burning. Thus heating the water in the radiators, resulting in an increase of the room temperature until it is higher than the desired temp. Then the control unit switches off your boiler, and so on. So, information about the room temperature is used by the control unit to regulate the boiler and thereby the room temperature – and thus the causal loop is closed.
Because this feedback system is trying to minimize the difference between actual and desired temperature we call this a negative feedback. You find this kind of controlling systems on many levels of your body, from gene regulation to homeostasis (all kind of processes like controlling body temperature and glucose concentration in the blood). Glucose concentration is maintained within some variation on a certain level by two feedback systems, one controlled by insulin to prevent glucose concentration getting too high and the second to watch that it doesn’t get too low, controlled by glucagon.  

Negative feedback is stabilizing all kinds of biological processes. But organisms also use positive feedback for example to generate neural impulses. Positive feedback means that a closed loop enhances an incoming signal up to a maximum level. The best known example is the singing around (buzzing) of a microphone signal, when some sound or even noise from the speakers is picked up by the microphone. Global warming due to increase of CO2-concentrations is a process with positive feedback too. More CO2 in the atmosphere increases the global temperature resulting in permafrost to melt partially. This leads to a release of greenhouse gasses CO2 and methane. Causally this is a self-amplifying process and therefore a positive feedback loop.
 

Combinations of feedback loops and moving particles

Both electronic systems and biological networks may have combinations of negative and positive feedback loops. The most simple version creates electrical signals or molecule concentrations that vary in a waveform during time. One of them is our internal biological clock. More complex combinations of positive and negative feedback loops may result in a kind of memory, switching the output level of the system to a permanent high level after an initial, short input signal.
Much more fascinating things happen when positive and negative feedback loops are part of systems with a large collection of moving particles, for example biomolecules in a growing tissue. In physical, chemical, biological and ecological systems interactions between ‘particles’ can give rise to all kind of patterns or structures. Examples are: sand ripples, mackerel clouds (physical), the Belousov–Zhabotinsky reaction (chemical), skin patterns, limb structures (biological) and large scale stripes and spots in semi-arid areas (ecological) etcetera. To illustrate what is meant we will take a look the way skin patterns can be described by mathematical models. These were first described by Alan Turing in 1952 and applied to biological processes by Hans Meinhardt and Alfred Gierer since 1974. Philip Ball discusses Turing patterns in chapter 8 (p. 307-328, printed version) which shows many parallels to my own book chapters 13 (p. 197-201) and 15 (p. 264-273).
Turing patterns like zebra stripes are examples of self-organization. At the start of such processes two or more species of molecules are randomly distributed in the fluid between cells of a developing tissue. So the initial situation is one without any pattern. Specific interactions between the two types of molecules, called morphogens, ánd differences in diffusion velocities may lead to all kinds of patterns (see p. 198 De kosmos en het leven).
In these systems, one kind of morphogen is working as an activator: it promotes the production of its own type of morphogens. The activator therefore has a self-amplifying effect. In addition, the activator promotes also the production of inhibitor morphogens. The activator therefore acts as a catalyst for production of new activators and inhibitor molecules. On the other hand, the inhibitor molecules de-activate the production of new activator molecules. So we see two kinds of feedback: (1) positive feedback of the activator (green, figure 2 below) and (2) negative feedback of the inhibitor (red). 

Figure 2

Pattern formation occurs because morphogens A and B diffuse through the fluid between cells, with different speeds. A random, local increase of concentration activator A, communicates via cellular mechanism to gene A to raise its production, ultimately leading to more activator molecules and more inhibitors in the intercellular space. That would make no difference except when the burst of inhibitors B spreads much faster than the activators A. The result of this is a slowing down of the production of gene A in cells further away from the initial fluctuation (see figure 3). This leads to a decrease in activator concentration in these areas. So the initial random fluctuation leads to the formation of a wave pattern in the intercellular space, finally resulting in a fixed and stable pattern, stripes, dots or more complicated shapes.

Looking at these processes two remarkable things show up. The two populations of many morphogens manifest a collective behavior in the form of waves, extending across a whole tissue. And these waves are changing the behavior of genes, far down in the cell nucleus. So there is a top-down causation from pattern to genes. Just like the traffic jam as a whole restricts your behavior as an individual car driver. And of course it also works the other way around – individual genes are influencing the wave form. And furthermore those waves are phenomena resulting from physical mechanisms. So, in these processes, gene expression is controlled by physics! In my book I suggested to call this extra-genetic regulation.

Fig. 3 Concentrations of activator (green) and inhibitor (red)
versus position at different times.
A random fluctuation in the activator concentration
starts up a process of wave formation, resulting in a stable pattern.

Mathematical models can be used to simulate the processes of limb and finger pattern-formation. Finger patterns correspond to a wave of a morphogen called SOX9. At positions where the concentration of SOX9 rises above a genetically defined threshold this morphogen induces cell differentiation: mesenchymal stem cells transform into chondrocytes (cartilage cells). So the wave pattern in combination with gene activity induces a condensation of this pattern. 

What does it all mean?

This kind of morphological processes has been recognized in many different stages of embryonic and fetal development. In combination with physical mechanisms, positive and negative feedback loops between genes and their products can lead to pattern formation starting from a structureless situation. One could wonder what is the central feature leading to pattern formation? The genes, the morphogens, the laws of motion, the feedback loops, the cells? The answer may be strange: none of them is thé central part of the system. All of them are indispensable, be it that positive feedback is the generating ‘force’ of the process.
One of the most important conclusions is that genes neither program for a pixel like description of biological patterns nor for a kind of positional information – where genes are coding at which position a stripe of a pattern should start and end (as theorized by Lewis Wolpert). No, genes are coding for processes of pattern formation. Genes are not creating patterns, they are providing suitable parameters of pattern formation processes, which are physical of origin and therefore universal. Mutations may tune gene interactions in such a way that patterns and structures in the course of generations are optimally robust and flexible.
In short: genes don’t code for pattern pixels, nor for pattern global positions but for a pattern process. This means Ball is right in saying that genes don’t code for a blueprint. But genes located on DNA strings, transfer much of the information needed for pattern formation to next generations. So genes are indispensable as the memory of life and as tools for the variation of life forms. 

In many chapters of his book, Philip Ball demonstrates that these kind of processes can be identified at all levels of biological organization: genetic networks, cell fate decision, tissue formation, pattern and structure formation.

Final conclusion: Philip Ball has written a very illuminating book about How Life Works. I read a lot of new interesting things about known biological processes. I agree with his frequently repeated statement that genes don’t code for a blueprint of structures and shapes. The analysis of complex systems driven by feedback loops shows that genes work in combination with physical mechanisms for the formation of biological structures. Ball is right to emphasize that there is no linear route from genes to pattern. Causal interactions are running up and down, from pattern to genes and the other way around. But these multilevel interactions do not deny the importance of genes but emphasize them. Unfortunately, Ball does not give much attention to this fact, sometimes actually denying this. Since the causality of these formation processes is circular in nature it is impossible and unnecessary to discuss which of the components is most important. A gene centered view is ruled out by this view of life. And because feedback loops are essential for so many biological processes, circular causality may be called the third secret of life.

In a future blog I hope to discuss some chapters of Ball’s book demonstrating the importance of circular causality during embryonic development. 

 

References

Allostery: Jacob, Francois en Jacques Monod, ‘Genetic regulatory mechanisms in the synthesis of proteins’, J Mol Biol. 3, 1961, p. 318-56.

Feedback loops: Xiao-Jun Tian et al., ‘Interlinking positive and negative feedback loops creates a tunable motif in gene regulatory networks,’ Physical Review E, 80, 2009, 011926-1-8.

Feedback loops: Dong-Eun Chang et al., ‘Building biological memory by linking positive feedback loops,’ PNAS 107-1, 2010, p. 175–180.

Morphogenesis: Allen Turing, “The chemical basis of morphogenesis”, Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 237, 1952, p. 37-72.

Morphogenesis: Hans Meinhardt and Alfred Gierer, ‘Applications of a theory of biological pattern formation based on lateral inhibition’, Journal of Cell Science 15, 1974, p. 321-346.

Frans de Waal: dierenliefhebber die dieren at

Frans de Waal legt uit aan Janine Abbring
waarom hij vlees eet. 20 August 20 2017 (bron)

Gisteravond berichtte de NOS dat bioloog en primatoloog Frans de Waal op 75-jarige leeftijd overleden is in zijn woonplaats Atlanta in de VS. Alle persberichten over Frans de Waal noemen hem standaard "een van de meest vooraanstaande primatologen ter wereld." [1]. Journalisten nemen dat altijd van elkaar over. Ik dacht ook dat hij "een van de meest vooraanstaande primatologen ter wereld" was totdat ik op 20 augustus 2017 in een uitzending van Zomergasten Frans de Waal aan Janine Abbring hoorde uitleggen waarom hij vlees at (hier). Janine betrapte hem op een grote inconsistentie. Hij moest zich er uit redden met een smoes. Maar zij moest door met de uitzending en kon er niet dieper op in gaan. Ik hoor nooit over dit incident in de pers. Een incident dat meer zegt over zijn karakter dan al zijn boeken. Frans de Waal was de wetenschapper die verdedigde dat dieren ook gevoelens hadden en ondertussen vlees bleef eten.   

in plaats van vegetariërs en veganisten aan te vallen, had hij als vegetariër of veganist duizenden mensen kunnen inspireren hetzelfde te doen en daarmee miljoenen dieren een onwaardig lot hebben kunnen besparen.

Frans de Waal was degene die in de Zomergasten uitzending had gezegd:

"Wel, de hele natuur bestaat uit een levenscyclus: je hebt dieren die eten planten, je hebt dieren die eten dieren, je hebt planten die eten dieren, als wij doodgaan worden we opgegeten door dieren." (bron)

Het zou dus passend zijn als het lichaam van Frans de Waal in het bos gelegd werd om door wolven, raven en wormen opgegeten te worden. [2]

 

Update 25 April 2024

Sarah F. Brosnan (2024) Frans de Waal (1948–2024) Primatologist who brought animals and humans “a little closer” Science 25 April 2024 

Brosnan is a student of Frans de Waal.

Noten

1. In de media hoor je nooit dat er ook andere primatologen bestaan, zoals de onlangs overleden Christophe Boesch (1951–2024) die chimpanzees in het wild onderzocht in Afrika en zich inzette voor hun behoud. Nature schreef een obituary over hem. Boesch was van mening dat "studies of chimpanzees in captivity tended to have little relevance to understanding their behaviour in the wild." Frans de Waal deed onderzoek naar een chimpanzee kolonie in gevangenschap. Boesch werd op jonge leeftijd geïnspireerd door het boek King Solomon’s Ring (1949) van Nobelprijswinnaar Konrad Lorenz. Ik weet niet of de Waal daarnaar verwijst in zijn vele boeken. Frans de Waal heeft het vakgebied ethologie niet uitgevonden en bij mijn weten heeft hij zich nooit ingezet voor het behoud van chimpanzees in het wild. Wat waren zijn idealen? [21 maart 2024]
2. Deze paragraaf toegevoegd 22 April 2024.
   

 

Bronnen

Killing Animals in the Age of Empathy. Frans de Waal, a leading primatologist explains why he eats animals blog 26 Sept 2017 met het Zomergasten fragment. 

 

Frans De Waal uses a fallacy to defend eating meat. No empathy with animals. Not a vegan. video fragment 3 okt 2017 (1508 hits)

 

Nederlandse blogs

1. Frans de Waal wil stoppen én doorgaan met vlees eten. En hij heeft voor beide argumenten. 20 Oct 2017. "Gisteren vond ik een column van Frans de Waal 'Zijn vleeseters agressief?' in Psychologie Magazine, 1 november 2013"
2. Zijn wij slim genoeg om te begrijpen waarom Frans de Waal nog steeds vlees eet? De drogreden van Frans de Waal 12 Sep 2017. Hier geef ik het volledige transcript van het gesprek tussen Frans de Waal en Janine Abbring over het eten van dieren.
3. Toevalsvondst zet drogreden Frans de Waal op scherp  9 nov 2021. De Waal gebruikt de naturalistische drogreden om vlees eten te rechtvaardigen, maar ik ontdekte in zijn eigen 'Een tijd voor empathie' (paperback, 2009) staat de 'Naturalistische drogreden' expliciet beschreven (pagina 41,42).
   
4. Zo kijkt Frans de Waal naar mens en dier. VPRO Tegenlicht. Ik snap het niet. 20 april 2023. "Het reduceren van de bio-industrie lijkt me het meest logische."
5. Het nieuwe boek van Frans de Waal 'Mama’s laatste omhelzing' 17 juli 2019. ... de Waal bijna geen zoogdieren meer eet. Hij was toen 71 jaar.
   
6. Zeer kritische bespreking van het nieuwe boek van Frans de Waal in Nature vandaag (14 april 2016) 14 april 2016. gaat over: Are we smart enough to know how smart animals are? Het review is gratis te lezen op Nature website.
7. Is het nog steeds nodig om aan te tonen dat moraal geen bovennatuurlijke oorsprong heeft? 2 Oct 2013. Naar aanleiding van de rede ter gelegenheid van het eredoctoraat van de Universiteit Utrecht 26 maart 2013.
   
8. Frans de Waal houdt lezing in een uitverkocht Paradiso 25 maart 2013. Zondag 24 maart 2013 hield Frans de Waal een lezing ter gelegenheid van zijn nieuwe boek De Bonobo en de Tien Geboden.
9. Enige hulp bij het lezen van De Bonobo en de Tien Geboden, 17 april 2013.  "Ik beperk me in dit blog tot wat Frans de Waal in hoofdstuk twee schrijft over de bekende genoom onderzoeker Francis Collins."
   

Engelse blogs

1. I have put much effort into proving Frans de Waal committed the Naturalistic Fallacy. And then this happened.  8 Nov 2021 is Engelse versie mijn blog Toevalsvondst...
   
2. Killing Animals in the Age of Empathy. Frans de Waal, a leading primatologist explains why he eats animals blog 26 Sept 2017 met het Zomergasten fragment.
3. Frans de Waal: Mama's Last Hug. Emotions, Sentience, Morality, Meat, Vegetarianism, Veganism  29 July 2019
   

 

Frans de Waal

• Zijn vleeseters agressief? column in Psychologie magazine 1 november 2013 (Laatste update: 16 december 2019). Dit is een schokkende, ongekend laag-bij-de-grondse aanval op vegetariërs en  veganisten en een pseudowetenschappelijke verdediging van vleeseters.

 

Youtube

• You Eat Other Animals? | Sci-Fi Comedy Short Film | Vegan Aliens. korte film (3 min): aanbevolen!
  

A review of Philip Ball (2024) How Life Works. With Postscript.

"The aim of this book is to show why these metaphors are inadequate, why they need replacing, and why we will not understand how life works until we do. It also attempts to sketch out what might be put in their place." (Prologue, How Life Works, Philip Ball, 2024).

To explain 'How life works' is an extremely ambitious venture with a 2000 year history. But first: what are these metaphors? For example this one: DNA is 'the secret of life'. The Human Genome is said to be 'our own instruction book' and 'The Book of Life'. But according to Ball this is like looking into a dictionary to understand literature. My impression is that Ball is throwing 'the dictionary' (DNA, the genome) out the window. But we haven't even finished completing the dictionary, we don't know how many words there are and how the words are used.

My problem with Ball is that he overreacts in such an extreme degree that he tries to doubt the importance of the discovery of the structure of DNA by Watson and Crick in 1953 (see my previous blog). Tellingly, Ball relegates the 1962 Nobel Prize for DNA to a footnote. I can't say it better than Bergstrom and Dugatkin in their most recent Evolution textbook:

Bergstrom,Dugatkin (2023)

"For the better part of the past 4 billion years, desoxyribonucleic acid -DNA- has been the chemical underpinning of life on Earth. At a very basic level, it is changes in DNA sequences and DNA expression that underlie the process of biological evolution by driving changes in phenotype and causing differences in fitness." 

After a description of the Watson-Crick structure of DNA they continue:

"Pause for a moment and consider what is encapsulated into those last six sentences: It is a triumph of modern biology that we are capable of describing the stuff of life in such succinct terms." [2]

Furthermore, we have good reasons to claim that DNA is the only molecule capable of sustaining life and giving rise to millions of species. There are no known rivals. There is no alternative. It would be a huge error to dismiss DNA to explain life on earth.

Ball is not the first scientist to claim that DNA is not 'the secret of life'. Nearly 30 years ago Stuart Kauffman wrote:

"Life does not depend on the magic of Watson-Crick base pairing or any other specific template-replicating machinery." [3]

Nick Lane (2022) wrote: "genes did not 'invent' metabolism, but the reverse." [4], others have similar views [6].

One can't discuss biology and evolutionary biology if one doesn't get DNA right. Philip Ball downgrades DNA to an extreme degree. But both emphasizing and de-emphasizing DNA too much is a bad thing. Emphasizing DNA too much only occurs with claims like "DNA is the blueprint of life" [5] and "DNA copies itself", "DNA self-replication", "Gene self-replication". Let's have a closer look. 

Biologists know that these statements are only true in the cellular environment. Just as viruses can't self-replicate, 'our' DNA can't 'self-replicate'. DNA needs enzymes (polymerases) to replicate. Viruses need enzymes to replicate. This view creates a unity between viruses and 'our own' DNA. There is only a gradual difference in usefulness for the host (some claim that there are useful viruses).

No biologist ever said DNA is alive. It is a big but dead polymer. It's an archive, a library. Biologists know that DNA on its own is not sufficient to explain life. The reason is that life consists of three interconnected subsystems: a hereditary system (DNA,RNA), an energy producing subsystem (metabolism) and a boundary system (membrane):

The 3 parts of life according to Tibor Gánti [1]
1. chemical motor system = metabolism
2. chemical boundary system = cell membrane
3. chemical information system = heredity, DNA

It is immediately clear from this diagram that by definition only the total system can be called alive. DNA is a subsystem. So, it follows from the logic of this definition of life that DNA isn't alive. Furthermore, I didn't realize until now that our own DNA depends just as much as viruses on the cellular environment to do anything at all. I didn't see it in that way before. Viruses aren't alive. DNA isn't alive. Interestingly, it follows also that 'our'  DNA is a kind of 'parasite' of the cell. The cell, our cells are its hosts. So, not just DNA sequences such as transposons are parasitic. Paradoxically, the whole genome is a 'parasite'. A parasite requires a host. We are the host. Did I just rediscover Dawkins' selfish gene concept? By the way, the 'parasitic' nature of DNA is also the reason it can't be involved in the origin of life. In that sense DNA can't be the start of life.

vicious circle

In the cellular environment DNA is not 'the start of everything', despite the fact that according to Crick's famous 'Central Dogma' information flows from DNA to protein. That may be confusing for some. DNA is not the start of everything in the cell. A circle has no starting point. Proteins are always required In the processes of DNA-replication, DNA transcription, mRNA splicing and translation. Those proteins must be present and have been synthesized earlier on. Indeed they have been synthesized on the basis of information in DNA. And in order to read that information enzymes have to be present...etc. That's the circle. 

Strictly speaking genes do not 'control' development, because that suggests an active involvement of genes. Genes do not express themselves, they are being expressed. I agree with Ball's criticism that genes are not actively doing anything [6]. That's a gain.

However, Ball's main point is that in order to understand 'how life works' one must understand the biochemical and physical forces involved in the cell and the organism. In the chapters Networks, Cells, Tissue, Bodies, Rethinking medicine, dozens of genes pop up again and again:

Src, Int1, TNF, bicoid, caudal, even-skipped, Hunchback, Giant, Kruppel, Dkk2, Dkk4, FGF, Sonic hedgehog, HoxD13, FGFR3, EDAR, Hsp90, Notch, Otx, Hex, Wnt, Nodal, E-cadherin, SHH, Shroom, myosin II, NF1, NF2, chordin, BMP, TGF-β, Gata1, Gata2, GPU.1, Sinr, SinI, Oct4, Sox2, c-Myc, Klf4, FBn1, CFTR, TSLP, CTLA4, IL6R, HBB, SRY, Sox9, SF1, APP, BRCA1, BRCA2, p53, ZIC4, ...

Conclusion:

• If you can't tell a DNA-free, gene-free story, then don't pretend you can. 
• If you do tell a DNA-free, gene-free story, then what is its relevance to biology?
• If you need genes to tell your story, give them a proper place in your story.
  

For example Ball writes in chapter 8: 

"The discovery of 'patterning genes' for the early body plan transformed our understanding of how genes affect development, and won Nüsslein-Volhard and Wieschaus the 1995 Nobel Prize for physiology or medicine". 

Christiane Nüsslein-Volhard (2006)
Coming to Life
How Genes Drive Development

Indeed! There you have it. According to the Nobel Prize website they "succeeded in identifying and classifying the 15 genes that direct the cells to form a new fly." So, 1) it's all about genes, 2) if genes are the words of the dictionary, then they discovered the meaning of those words. Those 'blueprint-geneticists' discovered which genes  are used in the early embryonic development, and when and where they are used. They discovered not only isolated words, but the context in which they are used. They are making significant progress in understanding important sentences of the 'language of life' (Francis Collins: 'the language of God'). It is part of 'how life works'. This research is opening the black box of development (see Fig. 2.1 in Ball's book).

Anyway, there are no gradients without gene products. Alan Turing invoked hypothetical morphogens and gradients. Those 'blueprint-geneticists' proved that morphogens do exist. Just as those 'blueprint-geneticists' have proven that Mendels hypothetical factors do exist. That is science. That is progress.

There is a lot more to say. But this is enough for today. I invited a physicist to comment on the physical aspects of How Life Works.

 

Postscript: a contradiction

2 March

I discovered a few sentences in chapter 9 which seem to nullify everything Ball wrote in chapter 2 against the importance of DNA: 

"we each have within us a deep evolutionary memory embodied in our genomes. If these are not blueprints, they nevertheless do encode information shaped and inherited over eons that is indispensable to our formation."  chapter 9. 17/123

Well, in essence this is identical to my quote from Bergstrom-Dugatkin. ('eons' is in fact 3.5 billion years). Here, Ball describes the indispensability of DNA! Does it matter whether DNA is called a 'blueprint' or 'indispensable information'? What's the difference? He continues:

"To what extent life is dictated by this Darwinian memory and to what extent it can draw on spontaneous ordering mechanisms is one of the central questions for understanding how it works."  

Indeed, that seems to be the central question of the book How Life Works. It's all about the relative importance of DNA and spontaneous order. Both are indispensable. Then, why write a whole book to downplay DNA? Maybe, the consensus view in biology is that DNA is the most important cause of the creation of an organism?

 

Notes

1. Tibor Gánti (2003) The Principles of Life. See: my review. Ball points out that a living entity must have a boundary of some kind (Ch 9. 83/123)
   
2. Bergstrom, Dugatkin (2023) Evolution, p 189. (textbook) see my website.
3. Stuart Kauffman (1995) 'At Home in the Universe. The Search for Laws of Self-Organization and Complexity' (my review). Ball doesn't mention Kauffman's book.
4. Nick Lane (2022) Transformer: The Deep Chemistry of Life and Death.
5. No biologist uses 'Blueprint of life' literally. That's impossible: DNA is a linear sequence. A cell is 3-dimensional object. In a review of How Life Works Denis Noble wrote "It’s time to admit that genes are not the blueprint for life" (Nature). Fine, what are genes really?
6. Ball quotes Richard Lewontin (1992): "Not only is DNA incapable of making copies of itself, but it is incapable of 'making' anything else." (end of Chapter 2) [1 March 2024]

 

Blogs about How Life Works

• A review of Philip Ball (2024) How Life Works. With Postscript 29 Feb 2024
  
• The Secret of Life according to Philip Ball, 19 Feb 2024
• What's wrong with a DNA-centric view? Philip Ball (2024) How Life works, 12 Feb 2024.  

 

Reviews by others

• Adam Rutherford: How Life Works by Philip Ball review – the magic of biology. The Guardian, 11 Jan 2024.
•