Tag Archives: blind watchmaker

Why you do and don’t need chemistry to understand why we have big brains

You need some serious molecular biological chops to understand why primates such as ourselves have large brains. For this you need organic chemistry. Or do you? Yes and no. Yes to understand how the players are built and how they interact. No because it can be explained without any chemistry at all. In fact, the mechanism is even clearer that way.

It’s an exercise in pure logic. David Hilbert, one of the major mathematicians at the dawn of the 20th century famously said about geometry — “One must be able to say at all times–instead of points, straight lines, and planes–tables, chairs, and beer mugs”. The relationships between the objects of geometry were far more crucial to him than the objects themselves. We’ll take the same tack here.

So instead of the nucleotides Uridine (U), Adenine (A), Guanine (G), Cytosine (C), we’re going to talk about lock and key and hook and eye.

We’re going to talk about long chains of these four items. The order is crucial Two long chains of them can pair up only only if there are segments on each where the locks on one pair with the keys on the other and the hooks with the eyes. How many possible combinations of the four are there on a chain of 20 — just 4^20 or 2^40 = 1,099,511,621,776. So to get two randomly chosen chains to pair up exactly is pretty unlikely, unless in some way you or the blind Watchmaker chose them to do so.

Now you need a Turing machine to take a long string of these 4 items and turn it into a protein. In the case of the crucial Notch protein the string of locks, keys, hooks and eyes contains at least 5,000 of them, and their order is important, just as the order of letters in a word is crucial for its meaning (consider united and untied).

The cell has tons of such Turing machines (called ribosomes) and lots of copies of strings coding for Notch (called Notch mRNAs).

The more Notch protein around in the developing brain, the more the proliferating precursors to neurons proliferate before differentiating into neurons, resulting in a bigger brain.

The Notch string doesn’t all code for protein, at one end is a stretch of locks, keys, hooks and eyes which bind other strings, which when bound cause the Notch string to be degraded, mean less Notch and a smaller brain. The other strings are about 20 long and are called microRNAs.

So to get more Notch and a bigger brain, you need to decrease the number of microRNAs specifically binding to the Notch string. One particular microRNA (called miR-143-3p) has it in for the Notch string. So how did primates get rid of miR-143-3p they have an insert (unique to them) in another string which contains 16 binding sites for miR-143-3p. So this string called lincND essentially acts as a sponge for miR-143-3p meaning it can’t get to the Notch string, meaning that neuronal precursor cells proliferate more, and primate brains get bigger.

So can you forget organic chemistry if you want to understand why we have big brains? In the above sense you can. Your understanding won’t be particularly rich, but it will be at a level where chemical explanation is powerless.

No amount of understanding of polyribonucleotide double helices will tell you why a particular choice out of the 1,099,511,621,776 possible strings of 20 will be important. Literally we have moved from physicality to the realm of pure ideas, crossing the Cartesian dichotomy in the process.

Here’s a copy of the original post with lots of chemistry in it and all the references you need to get the molecular biological chops you’ll need.

Why our brains are large: the elegance of its molecular biology

Primates have much larger brains in proportion to their body size than other mammals. Here’s why. The mechanism is incredibly elegant. Unfortunately, you must put a sizable chunk of recent molecular biology under your belt before you can comprehend it. Anyone can listen to Mozart without knowing how to read or write music. Not so here.

I doubt that anyone can start from ground zero and climb all the way up, but here is all the background you need to comprehend what follows. Start here — https://luysii.wordpress.com/2010/07/07/molecular-biology-survival-guide-for-chemists-i-dna-and-protein-coding-gene-structure/
and follow the links (there are 5 more articles).

Also you should be conversant with competitive endogenous RNA (ceRNA) — here’s a link — https://luysii.wordpress.com/2014/01/20/why-drug-discovery-is-so-hard-reason-24-is-the-3-untranslated-region-of-every-protein-a-cerna/

Also you should understand what microRNAs are — we’re still discovering all the things they do — here’s the background you need — https://luysii.wordpress.com/2015/03/22/why-drug-discovery-is-so-hard-reason-26-were-discovering-new-players-all-the-time/weith.

Still game?

Now we must delve into the embryology of the brain, something few chemists or nonbiological type scientists have dealt with.

You’ve probably heard of the term ‘water on the brain’. This refers to enlargement of the ventricular system, a series of cavities in all our brains. In the fetus, all nearly all our neurons are formed from cells called neuronal precursor cells (NPCs) lining the fetal ventricle. Once formed they migrate to their final positions.

Each NPC has two choices — Choice #1 –divide into two NPCs, or Choice #2 — divide into an NPC and a daughter cell which will divide no further, but which will mature, migrate and become an adult neuron. So to get a big brain make NPCs adopt choice #1.

This is essentially a choice between proliferation and maturation. It doesn’t take many doublings of a NPC to eventually make a lot of neurons. Naturally cancer biologists are very interested in the mechanism of this choice.

Well to make a long story short, there is a protein called NOTCH — vitally important in embryology and in cancer biology which, when present, causes NPCs to make choice #1. So to make a big brain keep Notch around.

Well we know that some microRNAs bind to the mRNA for NOTCH which helps speed its degradation, meaning less NOTCH protein. One such microRNA is called miR-143-3p.

We also know that the brain contains a lncRNA called lncND (ND for Neural Development). The incredible elegance is that there is a primate specific insert in lncND which contains 16 (yes 16) binding sites for miR-143-3p. So lncND acts as a sponge for miR-143-3p meaning it can’t bind to the mRNA for NOTCH, meaning that there is more NOTCH around. Is this elegant or what. Let’s hear it for the Blind Watchmaker, assuming you have the faith to believe in such things.

Fortunately lncND is confined to the brain, otherwise we’d all be dead of cancer.

Should you want to read about this, here’s the reference [ Neuron vol. 90 pp. 1141 – 1143, 1255 – 1262 ’16 ] where there’s a lot more.

Historically, this was one of the criticisms of the Star Wars Missile Defense — the Russians wouldn’t send over a few missles, they’d send hundreds which would act as sponges to our defense. Whether or not attempting to put Star Wars in place led to Russia’s demise is debatable, but a society where it was a crime to own a copying machine, could never compete technically to produce such a thing.

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Why our brains are large: the elegance of its molecular biology

Primates have much larger brains in proportion to their body size than other mammals. Here’s why. The mechanism is incredibly elegant. Unfortunately, you must put a sizable chunk of recent molecular biology under your belt before you can comprehend it. Anyone can listen to Mozart without knowing how to read or write music. Not so here.

I doubt that anyone can start from ground zero and climb all the way up, but here is all the background you need to comprehend what follows. Start here — https://luysii.wordpress.com/2010/07/07/molecular-biology-survival-guide-for-chemists-i-dna-and-protein-coding-gene-structure/
and follow the links (there are 5 more articles).

Also you should be conversant with competitive endogenous RNA (ceRNA) — here’s a link — https://luysii.wordpress.com/2014/01/20/why-drug-discovery-is-so-hard-reason-24-is-the-3-untranslated-region-of-every-protein-a-cerna/

Also you should understand what microRNAs are — we’re still discovering all the things they do — here’s the background you need — https://luysii.wordpress.com/2015/03/22/why-drug-discovery-is-so-hard-reason-26-were-discovering-new-players-all-the-time/weith.

Still game?

Now we must delve into the embryology of the brain, something few chemists or nonbiological type scientists have dealt with.

You’ve probably heard of the term ‘water on the brain’. This refers to enlargement of the ventricular system, a series of cavities in all our brains. In the fetus, all nearly all our neurons are formed from cells called neuronal precursor cells (NPCs) lining the fetal ventricle. Once formed they migrate to their final positions.

Each NPC has two choices — Choice #1 –divide into two NPCs, or Choice #2 — divide into an NPC and a daughter cell which will divide no further, but which will mature, migrate and become an adult neuron. So to get a big brain make NPCs adopt choice #1.

This is essentially a choice between proliferation and maturation. It doesn’t take many doublings of a NPC to eventually make a lot of neurons. Naturally cancer biologists are very interested in the mechanism of this choice.

Well to make a long story short, there is a protein called NOTCH — vitally important in embryology and in cancer biology which, when present, causes NPCs to make choice #1. So to make a big brain keep Notch around.

Well we know that some microRNAs bind to the mRNA for NOTCH which helps speed its degradation, meaning less NOTCH protein. One such microRNA is called miR-143-3p.

We also know that the brain contains a lncRNA called lncND (ND for Neural Development). The incredible elegance is that there is a primate specific insert in lncND which contains 16 (yes 16) binding sites for miR-143-3p. So lncND acts as a sponge for miR-143-3p meaning it can’t bind to the mRNA for NOTCH, meaning that there is more NOTCH around. Is this elegant or what. Let’s hear it for the Blind Watchmaker, assuming you have the faith to believe in such things.

Fortunately lncND is confined to the brain, otherwise we’d all be dead of cancer.

Should you want to read about this, here’s the reference [ Neuron vol. 90 pp. 1141 – 1143, 1255 – 1262 ’16 ] where there’s a lot more.

Historically, this was one of the criticisms of the Star Wars Missile Defense — the Russians wouldn’t send over a few missles, they’d send hundreds which would act as sponges to our defense. Whether or not attempting to put Star Wars in place led to Russia’s demise is debatable, but a society where it was a crime to own a copying machine, could never compete technically to produce such a thing.

Are you as smart as the (inanimate) blind watchmaker

Here’s a problem the cell has solved. Can you? Figure out a way to send a protein to two different membranes in the cell (the membrane encoding it { aka the plasma membrane }, and the endoplasmic reticulum) in the proportions you wish.

The proteins must have exactly the same sequence and content of amino acids, ruling out alternative splicing of exons in the mRNA (if this is Greek to you have a look at the following post — https://luysii.wordpress.com/2012/01/09/molecular-biology-survival-guide-for-chemists-v-the-ribosome/ and the others collected under — https://luysii.wordpress.com/category/molecular-biology-survival-guide/).

The following article tells you how the cell does it. Recall that not all of the messenger RNA (mRNA) is translated into protein. The ribosome latches on to the 5′ end of the mRNA,  subsequently moving toward the 3′ end until it finds the initiator codon (AUG which codes for methionine). This means that there is a 5′ untranslated region (5′ UTR). It then continues moving 3′ ward stitching amino acids together.  Similarly after the ribosome reaches the last codon (one of 3 stop codons) there is a 3′ untranslated region (3′ UTR) of the mRNA. The 3′ UTR isn’t left alone but is cleaved and a polyAdenine tail added to it. The 3′ UTR is where most microRNAs bind controlling mRNA stability (hence the amount of protein produced from a given mRNA).

The trick used by the cell is described in [ Nature vol. 522 pp. 363 – 367 ’15 ]. The 3’UTR is alternatively processed producing a variety of short and long 3’UTRs. One such protein where this happens is CD47 — which is found on the surface of most cells where it stops the cell from being eaten by scavenger cells such as macrophages. The long 3′ UTR of CD47 allows efficient cell surface expression, while the short 3′ UTR localizes it to the endoplasmic reticulum.

How could this possibly work? Once the protein is translated by the ribosome, it leaves the ribosome and the mRNA doesn’t it? Not quite.

They say that the long 3′ UTR of CD47 acts as a scaffold to recruit a protein complex which contains HuR (aka ELAVL1), an RNA binding protein and SET to the site of translation. The allows interaction of SET with the newly translated cytoplasmic domains of CD47, resulting in subsequent translocation of CD47 to the plasma membrane via activated RAC1.

The short 3′ UTR of CD47 doesn’t have the sequence binding HuR and SET, so CD47 doesn’t get to the plasma membrane, rather to the endoplasmic reticulum.

The mechanism may be quite general as HuR binds to thousands of mRNAs. The paper gives two more examples of proteins where this happens.

It’s also worth noting that all this exquisite control, does NOT involve covalent bond formation and breakage (e.g. not what we consider classic chemical reactions). Instead it’s the dance of one large molecular object binding to another in other ways. The classic chemist isn’t smiling. The physical chemist is.

Making an enzyme do a carbene reaction

The P450 cytochrome enzymes are the chemical workhorses of biosynthesis and xenobiotic detoxification.  As a neurologist I always had to worry about the way adding a new anticonvulsant to a an existing set would alter the body levels of all of them.  The new anticonvulsant would cause the P450 cytochrome enzyme metabolizing it to increase, and the new P450 might also chew up some of the others.  Phenobarbital was a particular problem this way.

Over 14,500 P450 genes have been found in various organisms. FYI the 450 in P450 comes from the absorption at 4500 Angstroms of the Fe++ in the heme group when complexed to carbon monoxide.  This is called the Soret band.  The P450 cytochromes are a superfamily comprising 36 known gene families, each consisting of 2 -20 discrete cytochromes.

The P450 cytochromes take 2 electrons from a reduced cofactor (NADPH) which itself gets the electrons from another molecule.  The cytochrome then binds an oxygen molecule splitting it so an oxygen atom is bound to the Fe++  (the other oxygen goes to water).  The oxygen is then used by the various enzymes to insert into C-H bonds with an incredible specificity (this produced by the conformation of the protein around the heme-iron-oxygen).

In Science vol. 339 pp. 283 – 284, 307 – 310 ’13 a group at Caltech which has been using direct evolution (randomly mutate a protein and select for the reaction you want) used a P450 cytochrome to accept diazo esters as reagents.  This formed a carbene linked to the Fe.  They found that it would add to olefins.  Further engineering (random selection actually) produced variants of the P450 to produce diastereoselective and enantioselective cyclopropanation of styrene.

It would be nice to see the crystal structures of the engineered enzymes carrying out the reactions, to see how they constrain the styrene to react so specifically.

So here we have chemists acting like the blind watchmaker of Dawkins.  It would be nice if theory was good enough to predict and design the P450 variants produced here a prioi, but it isn’t.  The editorialist calls it biomimicry in reverse.