Chirality is Just Turtles All the Way Down
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- Опубликовано: 7 июл 2024
- L-DOPA is the best drug we have for Parkinson’s disease. If you take L-DOPA and reflect it in a mirror, you get a different molecule: D-DOPA, which does absolutely nothing for Parkinson’s and causes potentially deadly side effects. Making just L-DOPA without D-DOPA is surprisingly hard - so hard that the person who finally figured out how to do it won the 2001 Nobel Prize in Chemistry.
00:00 Intro
00:35 Chirality
02:25 Racemic drugs
02:44 Parkinson’s disease
03:56 Option 2
07:02 The 2001 Nobel
09:03 Turtles all the way down
#ParkinsonsDisease #Parkinsons #LDOPA #DDOPA #Chirality #Enantiomers #NobelPrizeChemistry #DrugSynthesis #PharmaceuticalChemistry #Pharma #ChemicalReactions #Chemistry #OriginsOfLife #TurtlesAllTheWayDown
Credits:
Executive Producer:
Matthew Radcliff
Producers:
Andrew Sobey
Elaine Seward
Darren Weaver
Writers:
George Zaidan
Hosts:
George Zaidan
Scientific Consultants:
Eric Jacobsen Ph.D.
Brianne Raccor, Ph.D.
Michelle Boucher, Ph.D.
Executive in Charge for PBS: Maribel Lopez
Director of Programming for PBS: Gabrielle Ewing
Assistant Director of Programming for PBS: John Campbell
Reactions is a production of the American Chemical Society.
© 2024 American Chemical Society. All rights reserved.
Sources:
docs.google.com/document/d/1_... 
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4D creatures watching this are like "I don't get it, they're the same thing, you can flip it"
So true
Until they try to build a 4D molecule. A transformation matrix can always have a negative determinant.
I think chirality would extend into higher dimensions....in fact, wouldn't it add more possible isomers?
@@stevengill1736 the same way a 2D "chiral" molecule (i.e. a molecule that can be drawn in two or more ways such that translation of rotation can't make them overlap) becomes trivial to turn achiral in 3D, a 3D chiral molecule would be trivial to turn achiral in 4D. Of course, there would be 4D chiral molecules that wouldn't be in 5D and so on.
Take for example 1,2,4-trimethylbenzene, an achiral molecule: if you draw two of them on two pieces of paper (and I recommend you do!) you'll find that, without lifting the piece of paper, it's impossible to make them overlap. But if you lift the piece of paper and flip it, functionally moving the molecule into 3D space (1,2,4-trimethylbenzene is planar, so this works out nicely), you'll find that it's easy to do so!
Thinking about higher dimensions is weird, so the best we can do is reason by induction of how things behave going from 2d to 3d
@@stevengill1736 The molecule is a 3D object, but it would have to be 4D to be chiral for a 4D creature. But a 4D creature could rotate the molecule around a 4th dimension we don't have access too.
Like if you imagine a 2D creature with an axe that's facing right, there would be no way to rotate or move that axe in 2D to get it to face left, but we can take the 2D axe and flip it in the 3rd dimension to make it face left.
As a physicist, this stuff is fascinating to me because, yes! Parity symmetry is conserved in almost every interaction in the universe (the _only_ interaction we know of that breaks this rule is the weak force aka nuclear beta decay), so if you want a chiral object you need to _start_ with a chiral object but how do you even get that chiral object in the first place? We don't know! Some process spontaneously broke that symmetry while first building the structure of life and we have no clue what it was.
Considering life replicating is a roughly exponential process, small fluctuations due to pure chance could've been amplified to a huge difference. At some point, the entire environment gets dominated by a single chirality and evolution will eliminate the other.
Small clarification: the universe can easily generate 50:50 mixes of chiral chemicals. How the world ended up with an excess of one form over another is the weird question.
@@rkeil3145...now do it with all protein catalysts in a li'l sea of r-peptides with varying r-sugar decorations.
@@passerby4507 yeah "extreme dependence on initial conditions"
There's a video on YT of chemists demonstrating that the magnetite rich pools in which early life-molecules formed create sufficient bias to create chirality, and from there it is the simple fact that only molecules with appropriate chirality to have efficient interactions will be formed. Absent the polarisation bias, the precursor life molecule (RAO) is racemic.
I presume that other molecules, if created not in the original context, but in controlled lab reactions, without influences toward chirality like presence of single enantiomers, tend to always be racemic in output...?
The cute dog is a vital collaborator in this video and he should be credited
That's Caper, PhD ABD
If I slap you with my left hand, it won't help with Parkinson's. If I slap you with my right hand, it won't help with Parkinson's either but it will hurt more. I'll take my chemistry degree now please.
In all seriousness, great vid -- thanks for making the effort to make something so interesting so accessible. I genuinely didn't "get" chirality before.
5:56 "Enanti-" comes from the greek έναντι, which means opposite and the suffix "-mer" from μέρος (meros) which means part. So the one part of two opposites
Now the concept makes sense 😊
Excellent... whenever I learn a new word, I'm like "is there a linguist in the house?"
Fellow language nerd, and I always think of how dextro- gives us dexterity. Super shady to those 'non-dexterous' lefties. Thanks for the rad info!
10/10 vids its unfortunate u guys dont have more viewers, these vids genuinely make me interested in chemistry as someone who prefers physics
It gets down to the most basic level of almost everything in nature of life itself, which makes me appreciate biochemistry even more 😊
yeah they have some viral videos but they themselves are not viral. Won't stop me from sharing their video tho.
Many minerals form crystal structures which are chiral, and these are able to selectively crystallize with one chirality (without twinning) given the right conditions. Though the formation of the initial seed crystal seems like it would still be a random chirality. For example, quartz crystals are chiral, as they contain helical arrangements of silicate units. (Not that chiral quartz crystals were involved in the origin of life)
One theory for abiogenesis is that clay minerals could catalyze some reactions that build up sequences of amino acids or RNA. Even though the clays involved aren't chiral (usually, defects are a different story), they can show preferences for catalyzing the reaction between two molecules of the same chirality over opposite chiralities, and different reaction rates for the two enantiomers. It has something to do with the stability of the complex of the monomers with the clay catalyst, though I don't know the details of how it ends up being asymmetric.
I haven’t heard that clay can help catalyze those types of reactions before. That helps with my head canon that all you really need for life to form is a bunch of amino acids in the same place and a lot of time
Nucleic acids are chiral. When they first showed up, you would have had a racemic mixture dissolved in seawater, but the first molecule of DNA/RNA to be part of a living organism would have had to have one chirality or the other, which then would have helped set the chirality for everything else in biological systems.
Kind of like matter and antimatter, but uhhh...different
Interesting theory! This makes me wonder if there was a time on earth where there could have been two enantiomers of life, but one just happened to outcompete the other :)
I wonder if anyone's tried making the other chirality of DNA, to see what happens
Yes, exactly......
@@recurvestickerdragon evil doppelganger
Another interesting pair of enantiomers:
Dextromethamphetamine (as well as a racemic mix) is meth.
Levomethamphetamine is the decongestant in Vicks VapoInhaler.
Nice, so before the FDA passed that guidance we could have been taking meth for our common cold
@justshanestuff yeah. Inhalers in the 50s literally had meth in them.
@@justshanestuff😁😁😁💪💪💪
@@justshanestuff
likely were, knowing how weird old drugs could be
Benzedrex inhalers were benzedrine - I didn't know they used methamphetamine in inhalers too....
"skip ahead to the next section" uh... there are no chapter markings
Oops sorry! Should be fixed now
@@ACSReactionsStill not fixed, at least on ipad
@@ACSReactionsThanks! Works for me now
Also L Dopa cross blood brain barrier much better like dexedrine than adderal
@@a.belladonna8316 Wrong thread?
Conspiracy theorist stoner voice:
“I see the chiral vectors, maaan!”
thalidomide is a very interesting example of "which part of the racemic mixture is dangerous?"
Wonder about this.
Talking to a drug researcher about how formulations of the same drug can be tolerated better/more effective, he made mention of enantiomers as well as additives that don't have to be disclosed as part of the formula (and all the minor modifications you can make to a molecule to qualify for new patents).
It was all this subterfuge to differentiate from generics.
There's a Goosebumps book where a magic mirror swaps the viewer with their evil reflection. When I got older and learned about the chirality of glucose, I wonder how long the reflection doppelgänger could've survived on our side of the mirror.
awesome lol
This is great. I've been trying to explain to my mum for the past year why her Dexibuprofen is more expensive than regular Ibuprofen, and she has not understood it at all. Perhaps you can get the message through better than I could.
Does the Dex version just isomerize into racemic mixture in the body?
Possible analogies: Gloves or shoes: A left one can't be turned into a right one and it turns out that it's hard to make chemistry not make equal numbers of each. Clocks: A pendulum that only swings from the middle to the right (or left). G*ns: Making a blunderbuss only hit the right half of a circular target when aimed squarely (uh) at the middle.
My favourite: Handwashing: It's much harder to wash just one hand than both at the same time.
Fun fact, it's not turtles all the way down! We have seen parity symmetry (chirality in chemistry) violations with reactions involving weak force interactions.
The discovery of this was also followed by a Nobel prize!
I'm glad you brought up the point that regulatory groups consider different handed molecules to be distinct. "Celexa's patent expiring? Let's make Lexapro!"
This is one of the coolest/most informative videos Reactions has made in a while, good shit
Thank you for this very easy to understand explanation of a very complicated subject.
There actually IS a way to recrystalize certain substances in order to get an enantiomeric excess! And that includes certain amino acids -- theorized as one of the mechanisms that created the initial enantiomeric excesses that led to the chiral biochemistry we know today.
Certain chiral molecules can be made to crystalize in a homoselective way, i.e. when the lattice energy of a chiral crystal is much lower than that for a racemic one, a racemic solution will naturally form distinct segregated crystal grains for each enantiomer as it crystalizes.
For some theoretical substance that forms especially large crystal grains in this way, it might be enough to then sort the grains mechanically in an optical sorter (under polarized light), and recycle the rejected chirality by re-dissolving, re-racemizing, and re-recrystalizing them with the next batch.
For others, you might need to crush the crystalized mass and mechanically separate out just a few grains under a polarized microscope, then use those grains as seed crystals to lower the energy barrier to then get _only_ the matching enantiomer in a racemic solution to crystalize out onto their substrate. Perfect homoselective recrystalization usually only happens under specific conditions -- the concentration of the desired enantiomer is large enough, the non-desired small enough -- but with the right solvent mix, temperature, etc, you can often get that to at least include a few-percent margin around 50/50 racemic -- and then, by continuously re-racemizing an fractionally-depleted 49/51 solution back to 50/50 in a continuous-flow process, you can get near 100% conversion from an initial racemic crude mixture into the desired enantiomer.
And, with a bit more complexity, this can also be made to work for materials that won't form exclusively homoselective crystals from any racemic solution, if you can still manage to get your seed crystals to grow at least a bit while other smaller crystals also form, so you can then separate these crystals from the bulk with a mesh sieve or optical sorter and use them again until they're large enough to be crush into more seed crystals.
Is this title a dated John Green reference or a timeless Hindu mythology reference?
Why not both?
Also, not dated at all since the Turtles all the Way Down movie just came out. 🎉
But what's all the way up?
Elephants and a disc.
@@ACSReactions _Sometimes you feel like a nut, sometimes don't; Old El Paso's got hard-tacos, and soft._
Pratchett
Sooo... The answer is yes? It's turtles all the way down? Enantiomers come from enantiomers come from enantiomers ... Ad infinitum? But we know that can't be true because life has a beginning
At some point way back when life first emerged there must have been some reaction that produced a little more of one enantiomer than the other. But what that reaction was or why it was enantioselective we don’t know
Attaching the nitrogen at specific points on the carbon to yielding a COMPLETELY different compound. THIS is why needs are expensive. THIS is what is soooooo awesome about chemistry! Dude, did you realize how awesome you are for making this video? ❤️❤️❤️❤️
This was really fascinating, thanks George and team!
I really liked showing the molecular models right next to each other. I usually see that illustrated when talking about chirality but showing it in 3D like that made it far easier to grasp.
I heard a story that sugar is chiral in it's calorie content, but not it's taste. D-Sugar being what nature makes and L-sugar being a 0 calorie sweetener that is physically and chemically the same.
I enjoy the visual presentation in this video. Pretty quick subscription gained :)
Yeah that was really interesting. Didn't know the history
Actually chiral molecules often crystallize differently. First ever parting of two enantiomers was done by hand, sorting the crystals of the stuff into two piles.
this yt channel is simply amazing
there’s actually a paper on astronomy(?!?!) by a Furkan Ozturk that explores magnetite-induced chirality from the ocean floor that might’ve broken homochirality and basically created life, crazy stuff
In principle, you could do the same thing with circularly polarized UV light. As a bonus, you don't need chiral molecules to create circularly polarized light, you just need a linear polarizer and a quarter wave plate. (Those are optically anisotropic, but have no "handedness". The "handedness" comes from the relative orientation of the polarizer and the quarter wave plate.)
Interesting! I guess that's why I take Levothyroxine, a synthetic form of a thyroid hormone I need to live, and not Dextrothyroxine, a cholesterol-lowering drug discontinued for causing heart problems.
Just got this notification. I had my final chemistry exam earlier today.
Great timing.
It is useful to note that there are some stereospecific processes that can separate enantiomeric mixtures of specific compounds. Most famous of these is Tartaric acid, the compound responsible for the discovery of chirality in the first place. When crystallized, synthetic Tartaric acid (in the form of Sodium Ammonium Tartaric Acid) will appear in 2 different crystals that are mirror images of one another; these can be manually (though very laboriously) separated under a microscope. A particularly dedicated chemist could feasible use this to create a whole host of compounds of a specific chirality.
Super cool video, love ur energy. Will show to my kids
Great video
This is good shit and no bullshit keep up the good work.
Love the foray into biochemistry and chirality there. Could also be that we just landed on that chirality.
L-DOPA?!
House MD reference.
So there is a good chance that if we find Alien life they might use different mirrored molecules and we would not be able eat alien plants and alien meat, even though the alien life also was carbon based lifeforms.🤔 If it is "Turtles All the Way Down" but only mirrors would alien life still look like life as we know it, just mirrored, or would it "look" completely different?
Well we know for example L sucrose can't be digested but it still tastes the same. I imagine they'd be able to digest L sucrose but not D sucrose.
Their DNA might helix in the opposite direction. Most of them would be left handed.
For synthesis of chiral molecules without chiral feedstock, could circularly polarized light be used to create a slight bias towards production of one enantiomer, and then the bias be amplified chemically?
In physics we have CP violation, also it is so hard to find supersymmetry particle, it seems universe are indeed asymmetrical
love your voice and the video.
Same for S-ALA (S-alpha-lipoic acid) and R-ALA (R-alpha-lipoic acid)
S-ALA or just ALA sold for cheap but practically is useless while R-ALA is extremely expensive.
Sometimes it sold in 50% - 50% S-ALA and R-ALA and it seems that not only S-ALA useless but it also inhibits R-ALA therapeutic effect.
Regarding your hammer analogy: I'm not Jewish but I've *heard* there is some old story in the Jewish scriptures about how one of the first thnigs God gave to blacksmiths was the first pair of tongs. This is because tongs are so integral to blacksmithing that nobody could imagine making a pair without having a pair to use in the smithing process.
Why are both the molecules at 0:55, the same? If you mirror image it and flip the bonds, they are the same isomer.
The thing I had been pronouncing wrong was racemic not enantiomer.
You know, there is a way for enantiomers to separate naturally. If a racemic mixture crystallizes, it will often produce separate crystals of the different enantiomers. This process does not require a turtle beneath it. If one of those crystals somehow gets separated and later redissolves... Hey presto, you have separated enantiomers under primordial conditions.
Very informative, as always, George. But please slow down in future for the hearing, visually and comprehension impaired. Keep up the great work 👍.
Macromolecules fold into higher order structures with their own emergent symmetry properties. In order that this process is reliable then the molecular ingredients must also be consistent. It’s like a dice game where the dice produce random results but you are allowed to keep the rolls that worked, and these then alter the context changing the likelihood (or value) of future rolls, until the system is sufficiently internally consistent that you could call the above scenario abiogenesis. It reminds me of the matter/antimatter question - where the the universe’s excess matter come from ?!
So a random fluctuation in the original racemic mixture of amino acids (?) caused a slight excess of one enantiomer, which grew exponentially by some kind of auto-catalysis and totally wiped out the other (family of) enantiomers. Do I understand this correctly?
Is there a meaningful difference between S/R and L/D? How do you know when to use which?
L/D is mostly used for sugars, amino acids and closely related molecules (like DOPA, which derives from tyrosine) due to tradition. It's an old, pretty weird system based on the fischer projection of these molecules. R/S meanwhile allows you to describe the chirality of any chiral center of any molecule. L/D describes entire enantiomers while R/S denotes the chirality of each individual chiral feature. R/S is even more powerful as it's not limited to chiral centers but can also handle stuff like axial chirality.
You should also note that the two systems are not 1:1. You can't convert D/L into R/S by some simple rule, you always have to check for each molecule (for example the standard L-amino acids are all S, except for L-cysteine, which is R). Both of these systems are completely separate from the +/- (sometimes also written d/l) system, which is based on the direction that light is rotated in by the molecule.
Great video.
1) what is your mirror set doing in your microwave? 2)they sell racimic vitamin E - dl-(alpha) tocopherol, and some amino acids. Why is this OK?
Nice
Can you think of a organic molecule that is mostly an electron cloud, and not a defined shape, but once the O- or OH- comes along, it shapes itself to a defined rigid shapes, which defines the chiral image (which side of a mirror) that amino acids and proteins build onto it? The bottom of the turtle...
Wow, when I started watching this video, I had no idea how amazing it is gonna be! Currently reading "How life works" by Philip Ball. He advocates strongly against information-theory view of the life. I like his argument, but at the same time, the idea that it is all an unbroken chain of chemical reactions dating back billions of years - is in some weird way elegant and enticing, almost purporseful.
What does he advocate instead?
Chirality is not only at the molecular level.
The right hand rule demonstrates that this is a feature of this SIDE of the temporal manifold.
This is why there are no atoms made of antiprotons and positrons on this SIDE of the temporal manifold.
Time is a compactified dimension one single Planck second in size. This is why there are limits of lambda and event horizon.
Limit theorem.
This is why there is conservation.
We are closed in the present moment.
This evolves a hyperplane of the present using Kuramoto synchrony.
Matter on one side and antimatter on the other.
How do spinors fit in
It's almost like biochemistry's version of all those physicists saying "hey! Where did all the antimatter go?"
Hi i understand amphetamine's dextro and levo thing but methylphenidate confusing me
I don't see why "wasting" 2/3rds or even more is that big an issue for drugs. Probably 99% of the cost of drug production is the R&D (and 99% of the price is inflated, but that's beside the point). The point is that the actual mass production is relatively cheap compared to the price of the product. If production costs you 4 or even 10x as much, as long as there isn't a cheaper competing method that's still perfectly commercially viable.
Besides, I'm sure someone somewhere will find some use for the byproducts. It would be a problem if they were effectively toxic waste that had to be stored indefinitely, but worst-case they can be broken down into more basic components (for example; burned)
If you make a ton of product and produce a ton of waste, you have to pay for that disposal somehow.
Less waste, more profit.
@@KaitouKaiju I'm not saying it doesn't improve the profit margins, just that the profit margins are so huge at least in relation to the production costs that it in no way impacts the commercial viability.
Think about it though. How much does it cost to dispose of a ton (1000kg) of material? For non-hazardous material, you're talking
@@Sotanaht01because it's about being able to offer less effective stuff to poor people.
The question of interest to me is why did life on Earth end up using levo amino acids instead of dextro? Was it equally probable, or is there some faint quantum effect that gently nudges the probability towards R(-) or what we call levo or left handed enantiomers?
I'd imagine it's favorable for proliferation for all life to have the same chirality and some piece of primordial soup reacted in a way more conducive to life in one chirality than it did in the other
As i practicing organic chemist, i can tell you beyond a doubt that his fly is unzipped.
6:35 you need to first react the racemic mixture with thionyl chloride and then bring in the alkoxide
5:00 d-dopa nh2 should be on dash
now i wanna learn about these eight different types of menthol. are they all cold? is there a colder one? can they be drugs? i have questions
The answer must be polarised light right?
What about Tartaric acid? It naturally occurs as a racemate but when it crystallizes the enantiomers separate and form unique crystal shapes that are enantiopure and can be visually separated. This is how Louis Pasteur discovered chirality.
Yeah, I was going to bring this up. There are some cases where recrystallisation will differentiate chirality. I would guess there are some cases where you could add in other molecules and produce more complex crystal structures that differentiate based on chirality too. You would still be producing both enantiomers, but it might be a useful technique in cases where you do want both, but separate. It could also be a useful technique for creating high purity final product. For catalysts this could be well worth it.
This is the bert chem video I ever watched!
Shouldn't the next turtle be below the last one?
0:45 These molecules are not mirror images.
Don't some racemic mixtures crystallize to form separate crystals of the enantiomers?
Not sure if they're mirror images, the blue thing has a completely different bond angle.
Not to mention, some of the hydrogen around the blue thing.
Oh, they're enantiomers, incase you didn't know 😅
And those are definitely tortoises.
I wish you'd call out the subgroup that aren't CNOH. Ph? MeO? Ac? Good ol' protective actinide groups, is best way.
Can someone explain to me what turtles specifically have to do with any of this?
There's a myth of the world being on the back of a turtle and then it's obviously asked what is that turtle standing on and so on many worlds of turtles
Hammers Stones 🪨
And
Magnetism 🧲
Here are the answers to the questions in the video
Maybe there actually wasn't a first single enantiomer but there was a racemic mixture of early life (likely mutually incompatible) until the group of life with a particular enantiomer wiped out the competition?
This presupposes that there were already separate groups of enantiomerically pure lifeforms so that one can triumph over the other. But the question is how such groups would come about in the first place. Why would there be groups that only use a single enantiomer instead of the entire population using exclusively racemic mixtures? Once you have an enantiomerically pure system, it's self-perpetuating, that's easy. But the question is how you get from the generally racemic nature of the universe to such a system. Proposing two of these systems doesn't answer the question how they would form in the first place.
I came across this video recently ehich claimed the mustery of natures enantioselectivity is solved. Basically they say that it was due to the iron sand/ particles present in the ocean and rivers durign early formation of earth which caused the enantioselectivity. There was also a paper published but i am not sure how true it is though.
It's called cracking chirality: the mystery of mirror molecules
The first hammer wasn’t made, it was found
The Awakenings
The bottom turtle is autocatalyzing.
Should be called "The dope on the DOPAs"
Wonderful! Now explain what it is that we don't understand about those first "turtles". Thanks for another great lesson.
- How was the first hammer made? A ROCK. How do you make an enantiomer if you need an enantiomer to make it? You use one that's easy to make or one that's already readily-available.
- I'm surprised you didn't mention thalidomide; that was a hard-learned lesson on enantiomers, more notorious than D-DOPA.
To answer your hammer question: A rock.
Yeah but who made the rock
@@KaitouKaiju it's rocks all the way down.
So basically we're trying to figure out how to do what nature solved millions of years ago
Yeah, we’re speed running it 😂
Neither molecule was pointing toward me. They were pointing toward the bottom and top of my screen...
Instructions unclear, synthesized racemic meth
I just don't understand why it was ever allowed for racemic mixtures to be considered the same drug. What was the reasoning for this?
It wasn't always understood that they had a chemical difference in the body, and when it first became known there was no way to separate the two so they'd always be together anyway.
im pretty sure i don't understand the turtle analogy
Leopold Horner never got the Nobel Price...
Well, what's Dopabean's story then?
the turtles wanted you to know - it's turtles all the way up...
OMG did the L-DOPA just prove God. Just kidding but also not kidding ;)
My guess is the weak force is the driving force of chirality in our nature, just like how the weak force breaks the parity symmetry.
What a poor explanation
So annoying
I pronounce the 't' in enantiomer same as the 't' in lotion. Sh