Tag Archives: Cartesian dichotomy

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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Old dog does new(ly discovered) tricks

One of the evolutionarily oldest enzyme classes is aaRS (for amino acyl tRNA synthetase). Every cell has them including bacteria. Life as we know it wouldn’t exist without them. Briefly they load tRNA with the appropriate amino acid. If this Greek to you, look at the first 3 articles in https://luysii.wordpress.com/category/molecular-biology-survival-guide/.

Amino acyl tRNA syntheses are enzymes of exquisite specificity, having to correctly match up 20 amino acids to some 61 different types of tRNAs. Mistakes in the selection of the correct amino acid occurs every 1/10,000 to 1/100,000, and in the selection of the correct tRNA every 1/1,000,000. The lower tRNA error rate is due to the fact that tRNAs are much larger than amino acids, and so more contacts between enzyme and tRNA are possible.

As the tree of life was ascended from bacteria over billions of years, 13 new protein domains which have no obvious association with aminoacylation have been added to AARS genes. More importantly, the additions have been maintained over the course of evolution (with no change in the primary function of the synthetase). Some of the new domains are appended to each of several synthetases, while others are specific to a single synthetase. The fact that they’ve been retained implies they are doing something that natural selection wants (teleology inevitably raises its ugly head with any serious discussion of molecular biology or cellular physiology — it’s impossible to avoid).

[ Science vol.345 pp 328 – 332 ’14 ] looked at what mRNAs some 37 different AARS genes were transcribed into. Six different human tissues were studied this way. Amazingly, 79% of the 66 in-frame splice variants removed or disrupted the aaRS catalytic domain. . The AARS for histidine had 8 inframe splice variants all of which removed the catalytic domain. 60/70 variants losing the catalytic domain (they call these catalytic nulls) retained at least one of the 13 added domains in higher eukaryotes. Some of the transcripts were tissue specific (e.g. present in some of the 6 tissues but not all).

Recent work has shown roles for specific AARSs in a variety of pathways — blood vessel formation, inflammation, immune response, apoptosis, tumor formation, p53 signaling. The process of producing a completely different function for a molecule is called exaptation — to contrast it with adaptation.

Up to now, when a given protein was found to have enzymatic activity, the book on what that protein did was closed (with the exception of the small GTPases). End of story. Yet here we have cells spending the metabolic energy to make an enzymatically dead protein (aaRSs are big — the one for alanine has nearly 1,000 amino acids). Teleology screams — what is it used for? It must be used for something! This is exactly where chemistry is silent. It can explain the incredible selectivity and sensitivity of the enzyme but not what it is ‘for’. We have crossed the Cartesian dualism between flesh and spirit.

Could this sort of thing be the tip of the iceberg? We know that splice variants of many proteins are common. Could other enzymes whose function was essentially settled once substrates were found, be doing the same thing? We may have only 20,000 or so protein coding genes, but 40,000, 60,000, . . . or more protein products of them, each with a different biological function.

So aaRSs are very old molecular biological dogs, who’ve been doing new tricks all along. We just weren’t smart enough to see them (’till now).

Novels may have only 7 basic plots, but molecular biology continues to surprise and enthrall.

Never stop thinking, never stop looking for an angle

Derek Lowe may soon be a very rich man if he owns some Vertex stock. An incredible pair of papers in the current Nature (vol. 505 pp. 492 – 493, 509 – 514 ’14, Science (vol 343 pp. 38 – 384, 428 – 432 ’14) has come up with a completely new way of possibly treating AIDs. Instead of attacking the virus, attack the cells it infects, and let them live (or at least die differently).

Now for some background. Cells within us are dying all the time. Red cells die within half a year, the cells in the lining of your gut die within a week and are replaced. None of this causes inflammation, and the cells die very quietly and are munched up by white cells. They even send out a signal to the white cells called an ‘eat me’ signal. The process is called apoptosis. It occurs big time during embryonic development, particularly in the nervous system. Neurons failing to make strong enough contacts effectively kill themselves.

Apoptosis is also called programmed cell death — the cell literally kills itself using enzymes called caspases to break down proteins, and other proteins to break down DNA.

We have evolved other ways for cell death to occur. Consider a cell infected by a bacterium or a virus. We don’t want it to go quietly. We want a lot of inflammatory white cells to get near it and mop up any organisms around. This type of cell death is called pyroptosis. It also uses caspases, but a different set.

You just can’t get away from teleological thinking in biology. We are always asking ‘what’s it for?’ Chemistry and physics can never answer questions like this. We’re back at the Cartesian dichotomy.

Which brings us to an unprecedented way to treat AIDS (or even prevent it).

As anyone conscious for the past 30 years knows, the AIDS virus (aka Human Immunodeficiency Virus 1 aka HIV1) destroys the immune system. It does so in many ways, but the major brunt of the disease falls on a type of white cell called a helper T cell. These cells carry a protein called CD4 on their surface, so for years docs have been counting their number as a prognostic sign, and, in earlier days, to tell them when to start treatment.

We know HIV1 infects CD4 positive (CD4+) T cells and kills them. What the papers show, is that this isn’t the way that most CD4+ cells die. Most (the papers estimate 95%) CD4+ cells die of an abortive HIV1 infection — the virus gets into the cell, starts making some of its DNA, and then the pyroptosis response occurs, causing inflammation, attracting more and more immune cells, which then get infected.

This provides a rather satisfying explanation of the chronic inflammation seen in AIDS in lymph nodes.

Vertex has a drug VX-765 which inhibits the caspase responsible for pyroptosis, but not those responsible for apoptosis. The structure is available (http://www.medkoo.com/Anticancer-trials/VX-765.html), and it looks like a protease inhibitor. Even better, VX-765 been used in humans (in phase II trials for something entirely different). It was well tolerated for 6 weeks anyway. Clearly, a lot more needs to be done before it’s brought to the FDA — how safe is it after a year, what are the long term side effects. But imagine that you could give this to someone newly infected with essentially normal CD4+ count to literally prevent the immunodeficiency, even if you weren’t getting rid of the virus.

Possibly a great advance. I love the deviousness of it all. Don’t attack the virus, but prevent cells it infects from dying in a particular way.

Never stop thinking. Hats off to those who thought of it.