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
   

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 te zien als 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 door middel van die afstandhouders. Fysiek contact. Helaas kan vacuümglas niet zonder die afstandhouders. Dus die lekkage is onvermijdelijk.

Die afstandhouders lijken dus een nadeel, maar bedacht moet worden dat dit glas getest wordt met afstandhouders. 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 3cm en 3,5 cm. 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'.

 

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 !