Science
Related: About this forumSynthetic connectivity, emergence, and self-regeneration in the network of prebiotic chemistry
The paper I'll discuss in this post is this one: Synthetic connectivity, emergence, and self-regeneration in the network of prebiotic chemistry (Wołos et al., Science 369, 1584 (2020) eaaw1955.
I was inspired to spend some time with this (full) paper by another post in this group, specifically this one: A New Chemical 'Tree of The Origins of Life' Reveals Our Possible Molecular Evolution (ScienceAlert) (Thank you eppur se muova!)
When I was a kid, planning an organic synthesis was largely a "seat of the pants" undertaking; one would look at a structure, and try to figure a series of disconnections that were available to bond formation using synthetic reactions of various types - the more you knew, the better you were able to plan these things - and one would talk to friends, advisors, bosses and also spend a long time in the library in the complex pathways to various leather bound "chemical abstracts" and their various kinds of indexes, find the relevant abstract, then search for the bound issue of the journal, only, often, to find that the particular paper was not the one you actually needed to accomplish the task. You'd work your way back until you had a plan using readily available starting materials.
Sometimes, your plan would actually work so far along the line, and you'd get ambitious and scale up, and then a flask would break, and boom...the pain...the pain...the pain...
You really had to think a lot in those days, and also consider the risks of wasting valuable materials.
You really had to think, and certain things had to be second nature.
Here's a problem, I pulled out of an old "exercise book," Ranganathan and Ranganathan, Academic Press, 1980, for problem 124. pg 42, on my bookshelf: The problem asked to propose a mechanism for the reaction that converted compound #4 into compound #10:
The paper, Chemistry of Santonic Acid. Oxidative and Reductive Modifications (Hortmann and Daniel, J. Org. Chem. 1972, 37, 26, 44464460) of course, gives an answer to the problem, a mechanism that seems quite reasonable, but the point of the exercise is to work it out yourself before being prodded by the paper.
Imagine someone asked you to make compound 10 with almost no information, other than what you learned in school? It's not too obvious...
This nice presentation, from K.C. Nicolaou shows classic "disconnection" thinking: [link:https://nicolaou.rice.edu/ppt_lectures/12_GERMANY_GENERAL.pdf|Total Synthesis of Natural Products of Biological
and Medicinal Importance]
It's been 30 years, maybe, since I planned a full synthesis; my career took a different path, but those were the "good old days." (Obviously not Lindsay Graham "Good Old Days" Up yours Lindsay.)
But when I was a kid, we used to go, like kids going to a big rock concert, to lectures by E.J. Corey, or D.H.R Barton, or Barry Trost, or K.C. Nicolaou or Roald Hoffman...
...sigh... Life is fun and then you die.
There are now, I'm sure a large number of computational programs to help design syntheses, and in fact, the paper referenced above, is about prebiotic chemistry, where the starting materials are simply the common "prebiotic" molecules spread across space. These programs probably use connectivity matrices of some kind or another - I don't know - my knowledge of programming is primitive at best, and to be honest, it's been decades since I thought about connectivity matrices.
I'm not sure if the link give more than the simple abstract or what is called the "structured abstract," to non-subscribers but the "structured abstract" has this conclusion:
Computer-generated reaction networks are useful in identifying synthetic routes to prebiotically relevant targets and are indispensable for the discovery of prebiotic chemical systems that are otherwise challenging to discern. As our network continues to grow by means of crowd-sourcing of newly validated prebiotic reactions, it will allow continued simulation of chemical genesis, beginning with molecules as simple as water, ammonia, and methane and leading to increasingly complex targets, including those of current interest in the chemical and pharmaceutical industries.
So there you have it...
The "structured abstract" includes this graphic:
The caption:
Computer simulation of plausible prebiotic reactions creates a network of molecules that are synthesizable from prebiotic feedstocks and establishes multiple unreportedbut now experimentally validatedsyntheses of prebiotic targets as well as self-regenerating cycles. In this schematic illustration, light blue nodes represent abiotic molecules, dark blue nodes represent molecules along newly discovered prebiotic syntheses of uric and citric acids, and red nodes represent other biotic molecules.
From the introduction:
Allchemys Life module uses 614 reaction rules (transforms) involving C, O, N, S, and P elements, grouped within 72 broader reaction classes. Inclusion of these rules in our set is contingent on the existence of literature-described examples that document their execution under generally accepted prebiotic conditions...
The authors, however, dodge the elephant in the room, chirality:
The authors begin their task by running the alchemy program for two hours on a "standard laptop computer," using a network of reactions that involved only carbon, hydrogen, oxygen, and sulfur and which limited the molecules "discovered" in silico to those with a molecular weight of less than 300 Daltons. This generated tens of thousands of molecules, 82 of which were "biotic," which they define as consisting of the following classes of molecules: "...amino acids and peptides, nucleobases and nucleosides, carbohydrates, and metabolites..."
Again, to beat a dead horse, lacking chirality, the molecules are only weakly "biotic" in nature as I see it, and remain so without the spontaneous generation of chirality through either kinetic or other means.
In this paper, the captions are rather long and pretty much tell much of the story:
Fig. 1 Biotic and abiotic molecules in the networkof prebiotic chemistry:
The caption:
Another graphic:
Fig. 2 The networks molecular content and synthetic connectivity.
The caption:
The authors note that the elimination of some classes of reaction classes does not necessarily preclude arriving at the full or nearly full set of biotic molecules as a generated in the full sized class reactions, whereas removing sets of reaction classes has a fairly profound effect on the the number of abiotic molecules generated.
Interestingly, the software is said to find new pathways to biotic molecules.
Fig. 3 Examples of known and newly identified syntheses within the network of prebiotic chemistry.
Now it gets interesting, because was is discussed is an abiotic example of something that characterizes many metabolic processes, cyclic reactions, the most famous of which is the citric acid (Krebs) cycle.
Reference 10 is this paper:
Synthesis and breakdown of universal metabolic precursors promoted by iron. (Muchowska, K.B., Varma, S.J. & Moran, J. Nature 569, 104107 (2019))
And finally, there is the issue of catalysis, which, to return to a point I made earlier, may include asymmetric catalysis.
We first discuss the finding that compounds created within the network can themselves act as catalysts of additional chemical reactions, all operative under prebiotic conditions, thereby substantially expanding the accessible prebiotic chemical space. To show this, we queried the network for known organocatalysts or bi- and tridentate metal chelators capable of binding metal cations present on primitive Earth [e.g., Cu(II), Zn(II), and Mn(II) (40)] and also used in modern organometallic catalysts. Figure 4A lists eight such catalysts enabling different reaction types and collectively more than doubling the size of the network. All of these reactions were previously carried out under prebiotic conditions (4148), but their relevance to OL was unnoticed.
Fig. 4 Chemical emergence in the network of prebiotic chemistry.
The caption:
IDA here is imidodiacetic acid, which is a derivative of the simplest amino acid, glycine, a "Siamese" glycine if you will. This molecule is an excellent chelator of metals, and as such, can coordinate metals which may act as catalysts.
The cyclic reaction detailed in the next figure, includes IDA in its pathway.
Fig. 5 Emergence of self-regenerating cycles within the network of prebiotic chemistry.
The caption:
The final piece of the puzzle is lipids, which of course make up cellular membranes, both for cells themselves and for intracellular organelles.
The caption:
Finally, the third class of emergence was the formation of surfactant molecules capable of spontaneously forming vesicles that could potentially house reactions and systems such as those described above. As illustrated in Fig. 6A, straight-chain saturated fatty acid and ?-hydroxy acid surfactants can form through repeated four-step cycles of aldehyde homologation. Breaking the cycle, the last step of fatty acid synthesis, may then occur via nitrile or thioamide hydrolysis to carboxylic acid. The aldehyde homologation cycle was proposed by Patel et al. (8) as a prebiotic method to make hydrophobic amino acids, but its straightforward extension to fatty acid surfactants was not noted in that report. In another and synthetically much shorter approach, peptide surfactants with variable glycine or alanine tails and aspartic acid head groups are available within only a few synthetic generations. Previously, such peptides had been synthesized by modern, nonprebiotic synthetic methods and had been shown (in the context of nanotechnology, not OL research) to form nanotubes and nanovesicles (64).
Fig. 6 Biomimetic routes to surfactants and additional pharmaceutically relevant scaffolds.
The caption:
The authors consider, in conclusion that their work may not only assist in approaching the intellectually satisfying question of the origins of life, but may well have practical import as well.
CatLady78
(1,041 posts)Btw NNadir, I cannot be more specific yet, but though it is very early days yet, you/eppur etc. and the science forum on du may have serendipitously helped me re:science immensely. Time will tell...can't say more yet...
I have met a very cool scientist mostly (in a roundabout way) because of a post I made here...what are the odds huh? Thanks for encouraging people to post here. Since I am skeptical about social media/most net use really by now, this could only have happened to me via good old du and I am grateful.
Even if nothing works out, any cool interaction with a fun scientist is net positive..
With gratitude,
CatLady78
NNadir
(33,464 posts)...scientific career, and/or allowed them to take pleasure and joy from it.
Thanks for letting us know, and you're very welcome.
CatLady78
(1,041 posts)You guys really helped me..long winded post but i do want to express my sincere gratitude. I am an introvert but even introverts appreciate rare instances of human contact (just not on vacuous tripe like Facebook). I am not
comfortable with too many people but a little respect and motivation from the rare sources help a lot.
I had some really great mentors and collaborators in the NiH system years ago...but I got burnt out because of the stresses of interdisciplinary work...no one to blame but myself...A few scientists tried to mentor me further (like a prof from ca in 2014), but at the end of the day only your own brain can help you. Nicholas Carr's work was eye opening re The Shallows of science I was navigating.
I was in a real slump and working on a paper I will submit by March 31, 2021. But I was bored and in a slump and while I used to track cool labs (all in Europe), it was gloomily while thinking i will never again work on anything fun again..
My work with my 1st postdoc mentor spoilt me for dull work. And rigourous work is hard and takes a mind at peace.
And then I forced myself to start posting here just to force myself to do a science journal club (since I trust you guys implicitly -you are not a Zuckerberg-Chan or a Google or other business education initiative or something hideous like that or "influencers" etc). You are just real Dems and this is a low visibility forum which makes it soothing. And predictably I made some errors- felt like Sarah Palin! And you NNadir specifically encouraged me to post regardless..and for once instead of curling up into a ball of shame, I read the paper through thoroughly, understood 85-90% of it and reposted it. Totally worth it because it was such cool work. Whether what I am doing now works out or not, it will be positive net as any interaction with a good scientist is a net positive.
Thank you for being such a friendly forum. You and smartpatients (a good group i found via du) are the only social media I recognize.
God I hope you are never bought up by Facebook, Google, Twitter, LinkedIn etc....i was bummed out when Skinner left and I have a gloomy feeling EarlG and Elad will be next. I hope they sell it to that DuckDuckgo guy, Gabriel Weinberg if they do....or to the Protonmail People..who all have to be Dems.
This really is a safe space for a liberal scientist.And while smart patients is apolitical, there is something so sobering about cancer, that trolls and creeps do not show up there....It is like the old internet..pre Facebook, Twitter etc...a real wild space...not a police state PanOpticon...
It is ineffable..the utility of normal decency...
CatLady78
(1,041 posts)It looks interesting. A little information dense as always but cool enough to grab one's attention..
You might like these papers NNadir (unless you are familiar with them).
Incidentally chirality(your elephant) is precisely what I am trying to write a grant on...
You may like this paper NNadir:
https://www.biorxiv.org/content/10.1101/349670v1
It is the first paper I have seen on how chirality might confer an actual fitness advantage...intriguing...
https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1006645
Chirality in shape and motility can evolve rapidly in microbes and cancer cells. To determine how chirality affects cell fitness, we developed a model of chiral growth in compact aggregates such as microbial colonies and solid tumors. Our model recapitulates previous experimental findings and shows that mutant cells can invade by increasing their chirality or switching their handedness. The invasion results either in a takeover or stable coexistence between the mutant and the ancestor depending on their relative chirality. For large chiralities, the coexistence is accompanied by strong intermixing between the cells, while spatial segregation occurs otherwise. We show that the competition within the aggregate is mediated by bulges in regions where the cells with different chiralities meet. The two-way coupling between aggregate shape and natural selection is described by the chiral Kardar-Parisi-Zhang equation coupled to the Burgers equation with multiplicative noise. We solve for the key features of this theory to explain the origin of selection on chirality. Overall, our work suggests that chirality could be an important ecological trait that mediates competition, invasion, and spatial structure in cellular populations.
Incidentally, cells grown on micropatterned surfaces reveal that cancer cells reverse their chirality:
https://www.pnas.org/content/108/30/12295
Micropatterned mammalian cells exhibit phenotype-specific left-right asymmetry.
Left-right (LR) asymmetry (handedness, chirality) is a well-conserved biological property of critical importance to normal development. Changes in orientation of the LR axis due to genetic or environmental factors can lead to malformations and disease. While the LR asymmetry of organs and whole organisms has been
extensively studied, little is known about the LR asymmetry at cellular and multicellular levels. Here we show that the cultivation of cell populations on micropatterns with defined boundaries reveals intrinsic cell chirality that can be readily determined by
image analysis of cell alignment and directional motion. By patterning 11 different types of cells on ring-shaped micropatterns of various sizes, we found that each cell type exhibited definite LR asymmetry (p value down to 10?185) that was different between normal and cancer cells of the same type, and not dependent on
surface chemistry, protein coating, or the orientation of the gravitational field. Interestingly, drugs interfering with actin but not microtubule function reversed the LR asymmetry in some cell types. Our results show that micropatterned cell populations exhibit phe-
notype-specific LR asymmetry that is dependent on the functionality of the actin cytoskeleton. We propose that micropatterning could potentially be used as an effective in vitro tool to study the initiation of LR asymmetry in cell populations, to diagnose disease, and to study factors involved with birth defects in laterality.
https://phys.org/news/2011-06-bioengineering-approach-tiny-cell-patterns.html
They found that the direction of motion depended on cell type that normal cells and cancer cells of the same type show opposite directions of motion, and that the mechanism by which the directional motion is established involves the actin stress fibers inside the cell. "What's really interesting about this work is that it shows that cells can establish a consistently biased asymmetry without the help of large-scale embryonic structures.
NNadir
(33,464 posts)Right now, besides other things, in my spare time, I'm a little removed from biochemical reflections I and am thinking about the chemical physics of clathrates.
That's what's keeping me amused while I'm trying not to worry about the fate of my country.
I am trying to write a grant proposal connecting cell chirality and cancer and trying not to think about other left-right asymmetries presently.
I am not in the United States and I do not ever plan to go back there but I cherish a fondness for the country and am saddened at the thought of what could happen..especially on account of the ecological consequences, the impact on the poor and the impact on science/the scientific community...
I cannot believe this obviously demented caricature and his crass, corrupt and sleazy coterie of creeps has a second shot.
The only industries that will benefit will be ones based on self-promotion...since that is quite evidently the only skill-set their leader has...a fitting satire wrt times we live in...still I am hoping Biden pulls it off...it should not be this close though.