Category Archives: Theological implications of simple chmistry

At a funeral

As I sat at a funeral for a friend’s wife 8 days ago, I thought how little the congregation (and most people) comprehend about we’ve been given.  The service was about eternal life and faith in it.  Faith isn’t easy apparently, and requires work to achieve and maintain.  While acquiring the chemistry, physics and math to understand molecular biology requires work, seeing it make accurate predictions and accepting the truth of the conceptual schemata required to even think of the experiments requires no faith at all

A bit about the deceased.  A lovely, talented, intelligent very beautiful woman who married a college classmate.  3 sons, 4 granddaughters as beautiful tall and graceful as she was. So she clearly has continuing (if not eternal) life.  When I first met her at our 50th college reunion, she appeared so young and so beautiful, that I immediately put my foot in my mouth and asked her if she was XXX’s second wife.

So I’m sitting there thinking about Duchenne dystrophy, and the transcription of the 2 million basepair gene for dystrophin with removal of 99.5% of the transcript before the mRNA is sent out the cytoplasm, wondering why we’re not all in wheelchairs, and how the congregation has no clue about any of this, as they sit there making and consuming their body weight in ATP over the course of a day.

Theodicy would no longer be a problem for the religious if they had any conception of just how miraculous our existence is.

Do molecular biologists have faith?  I think most do, since most appear to believe that intricate cellular metabolism and the molecular machines that make life possible just arose by random events with selection of the fittest.  Actually I don’t think that most think about these matters at all.  They certainly don’t publish about it, and doing so when I was a blogger for Nature Chemistry, got me bounced.

The more we find out about how we work internally, the more miraculous it becomes (to me at least) providing evidence for a creator.  It’s back to reverend Paley and the found watch.

I’ll close with this

It was pretty hard to be a doc back in the 60s and 70s watching good people suffer and die, and still conceive of a benevolent creator. “The Plague” by Camus with its hideous death scene of a child pretty much sums up the argument against one.

And yet, now that we know so much more molecular biology, cellular and organismal biochemistry and physiology, our existence seems totally miraculous. I at least have achieved a sense of peace about illness, suffering and death. These things seem natural. What is truly miraculous is that we are well and functional for so long.

You can take or leave the argument from design of Reverend Paley — here it is

“”In crossing a heath, suppose I pitched my foot against a stone, and were asked how the stone came to be there; I might possibly answer, that, for anything I knew to the contrary, it had lain there forever: nor would it perhaps be very easy to show the absurdity of this answer. But suppose I had found a watch upon the ground, and it should be inquired how the watch happened to be in that place; I should hardly think of the answer I had before given, that for anything I knew, the watch might have always been there. … There must have existed, at some time, and at some place or other, an artificer or artificers, who formed [the watch] for the purpose which we find it actually to answer; who comprehended its construction, and designed its use. … Every indication of contrivance, every manifestation of design, which existed in the watch, exists in the works of nature; with the difference, on the side of nature, of being greater or more, and that in a degree which exceeds all computation.”

The more chemistry and biochemistry I know about what’s going on inside us, the harder I find it to accept that this arose by chance.

This does not make me an anti-evoloutionist. One of the best arguments for evolution, is the evidence for descent with modification, one of its major tenets. The fact that we can use one of our proteins to replace one on yeast using our present genetic technology is hard to explain any other way.

Actually to me now, the existence or nonexistence of a creator is irrelevant. The facts of how we are built is not something you need faith about. The awe about it all comes naturally the more we know and the more we find out.

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Goodbye to the blind watchmaker — take I

The Michelson and Morley experiment destroyed the ether paradigm in 1887, but its replacement didn’t occur until Einstein’s special relativity in 1905.  One can disagree with a paradigm without being required to come up with something to replace it. Unfortunately, we tend to think in dichotomies, so disagreeing with the blind watchmaker hypothesis for life itself tends to place you in the life was created by some sort of conscious entity.  “Hypotheses non fingo”  (Latin for “I feign no hypotheses”) which is what  Newton famously said  when discussing action at a distance which his theory of gravity entailed (which he thought was pretty crazy).

Here are  summaries of four previous posts (with links) showing why I have problems accepting the blind watchmaker hypothesis.  These are not arguments from faith which nowhere appears, but deduction from experimental facts about the structures and processes which make life possible. Be warned.  This is hard core chemistry, biochemistry and molecular biology.

First the 20,000 or so proteins which make us up, a nearly vanishing fraction of the possible proteins.  For how vanishing see — https://luysii.wordpress.com/2009/12/20/how-many-proteins-can-be-made-using-the-entire-earth-mass-to-do-so/.  Just start with 20 amino acids, 400 dipeptides, 8000 tripeptides.  Make one molecule of each and see how long a protein you wind up with making all possibilities along the way.  The answer will surprise you.

Next the improbability of a protein having a single shape (or a few shapes) for some chemical arguments about this — see https://luysii.wordpress.com/2010/08/04/why-should-a-protein-have-just-one-shape-or-any-shape-for-that-matter/

After that — have a look at https://luysii.wordpress.com/2010/10/24/the-essential-strangeness-of-the-proteins-that-make-us-up/.

The following quote is from an old book on LISP programming (Let’s Talk LISP) by Laurent Siklossy.“Remember, if you don’t understand it right away, don’t worry. You never learn anything, you only get used to it.”   Basically I think biochemists got used to thinking of proteins have ‘a’ shape or a few shapes because that’s what they found when they studied them.

If you think of amino acids as letters, then proteins are paragraphs of them, but to have biochemical utility they must have ‘meaning’ e.g. a constant shape.

Obviously the ones making us do have shapes, but how common is this in the large universe of possible proteins.  Here is an experiment which might show us (or not)– https://luysii.wordpress.com/2010/08/08/a-chemical-gedanken-experiment/.

From a philosophical point of view, the experiment is quite specific.  From a practical point of view quite possible to start, but impossible to carry to completion.

Well this is a lot of reading to do (assuming anyone does it) and I’ll stop now (although there is more to come).

Why do this at all?  Because I’ve been around long enough to see authoritative statements (by very authoritative figures) crash and burn.  Most of them I didn’t believe at the time — here are a few

l. The club of Rome’s predictions

2. The population bomb of Ehrlich

3. Junk DNA

4. We are 98% Chimpanzee because our proteins are that similar.

5. Gunther Stent, very distinguished molecular biologist, writing that we were close to the end of our understanding of genetic biology.  This in 1969.

The links elaborate several reasons why I find the Blind Watchmaker hypothesis difficult to accept.  There is more to come.

“Hypotheses non fingo”

Let’s hear it for the blind watchmaker

The blind watchmaker had a lot of foresight in choosing to use a rather  funky looking amino acid (proline) resembling none of the others.  A lot of kindness was also shown to structural molecular biologists by two of the watchmaker’s henchmen – Burkholderia gladioli and the common daisy.

All appear in a fascinating paper [ Cell vol. 176 pp. 435 – 447  ’19 ] in which the structure and better the mechanism of action of the mitochondrial ADP/ATP translocase, a molecule of some interest since our mitochondria make our body weight of ATP each day and need some way to get it out into the cytoplasm where it is used.

The molecule has quite a job to do, getting the rather large ATP molecule out to the intermembrane space (and thence out to the cytoplasm) without allowing protons to sneak out with it, since it is the proton gradient which is used to power ATP synthase the exquisite machine which makes ATP.   This is quite a trick as no chemical moiety is as small as a proton.

The translocase has two states — one in which it is open to the mitochondrial matrix (called the m-state) and another in which it is open (eventually) to the cytoplasm — called the c-state. In the m-state the cytoplasmic portion is shut, and in the c-state the membrane portion is shut.

The rather wierd looking molecule bongkrekic acid  made by Burkholderia gladioli  https://en.wikipedia.org/wiki/Bongkrek_acid binds to the translocase fixing it in the m-state.  Atractyloside, made by daisies binds to the molecule fixing it in the c-state.  They made life much easier for the structural biologist and cryoEMographers who wrote the paper.

Proline comes in because when placed in an alpha helix, proline’s 5 membered ring structure fixes the alpha carbon so that it is essentially inflexible, meaning that it can’t get into the conformation that the other 19 amino acids can get into when an alpha helix is formed.  Translation — proline is a helix breaker, forming a kink in the helix.

The translocase contains 3 modules of 100 amino acids each of which has 2 alpha helices, one of them containing a proline causing a kink in the helix.  The prolines are in the middle of the helix.  The ATP channel is formed by the 6 helices.

Essentially in the middle of the membrane, the kinked alpha helices form a pivot (fulcrum), so the helices rock back and forth, opening one side while simultaneously shutting the other, permitting ATP to bind near the fulcrum without letting anything else through, when the pivot shifts   — out goes the ATP (without letting protons sneak past).

There is far more beautiful protein chemistry on display.  There is a conserved signature motif Proline x Aspartic acid/Glutamic acid X X Lysine/Arginine at the carboxy terminal end of one of the helices of each other 3 modules — this forms a salt bridge shutting the channel on the matrix side.  Glycine and other small amino acids (alanine) allow close packing of the helices on the cytoplasmic side.

It is unfortunate that the most of humanity doesn’t have the background to appreciate the elegance and beauty of Nature’s solution to the problem.  I say Nature rather than God to be scientifically correct, but it’s elegant chemistry like this that makes it hard for me to accept that it arose by the machinations of a blind watchmaker.

Thomas Gold lives !

Thomas Gold was a scientific jack of all trades being involved in physics, cosmology and geochemistry, the latter of interest to us here.  He thought petroleum and other hydrocarbons were actually produced by micro-organisms below the surface of the earth, providing us with a replenishable supply (how ecological !)  Here’s part of a Wiki article about him —  Hydrocarbons are not biology reworked by geology (as the traditional view would hold), but rather geology reworked by biology.– https://en.wikipedia.org/wiki/Thomas_Gold.

Why bring him up now?  Because [ Proc. Natl. Acad. Sci. vol. 115 pp. 10702 – 10707 ’18 ] (http://www.pnas.org/content/115/42/10702) showed that 600 meters below the surface (where light and molecular oxygen never go) Cyanobacteria were found.  They use the electrons stripped from hydrogen (which is said to be produced in the subsurface by several (unspecified) abiotic mechanisms) as an energy source.  The electrons have to go somewhere, and they postulate that the electron acceptors are iron or manganese oxides. Wherever microorganisms have been found in deep continental settings hydrogen concentration decreases.

Basically life acts as the middleman, taking an energy cut from the flow of electrons from reductant to oxidant.

Seriously, life may have actually arisen in such situations.

A creation myth

Sigmund Freud may have been wrong about penis envy, but most lower forms of scientific life (chemists, biologists) do have physics envy — myself included.  Most graduate chemists have taken a quantum mechanics course, if only to see where atomic and molecular orbitals come from.  Anyone doing physical chemistry has likely studied statistical mechanics. I was fortunate enough to audit one such course given by E. Bright Wilson (of Pauling and Wilson).

Although we no longer study physics per se, most of us read books about physics.  Two excellent such books have come out in the past year.  One is “What is Real?” — https://www.basicbooks.com/titles/adam-becker/what-is-real/9780465096053/, the other is “Lost in Math” by Sabine Hossenfelder whose blog on physics is always worth reading, both for herself and the heavies who comment on what she writes — http://backreaction.blogspot.com

Both books deserve a long discursive review here. But that’s for another time.  Briefly, Hossenfelder thinks that physics for the past 30 years has become so fascinated with elegant mathematical descriptions of nature, that theories are judged by their mathematical elegance and beauty, rather than agreement with experiment.  She acknowledges that the experiments are both difficult and expensive, and notes that it took a century for one such prediction (gravitational waves) to be confirmed.

The mathematics of physics can certainly be seductive, and even a lowly chemist such as myself has been bowled over by it.  Here is how it hit me

Budding chemists start out by learning that electrons like to be in filled shells. The first shell has 2 elements, the next 2 + 6 elements etc. etc. It allows the neophyte to make some sense of the periodic table (as long as they deal with low atomic numbers — why the 4s electrons are of lower energy than the 3d electons still seems quite ad hoc to me). Later on we were told that this is because of quantum numbers n, l, m and s. Then we learn that atomic orbitals have shapes, in some wierd way determined by the quantum numbers, etc. etc.

Recursion relations are no stranger to the differential equations course, where you learn to (tediously) find them for a polynomial series solution for the differential equation at hand. I never really understood them, but I could use them (like far too much math that I took back in college).

So it wasn’t a shock when the QM instructor back in 1961 got to them in the course of solving the Schrodinger equation for the hydrogen atom (with it’s radially symmetric potential). First the equation had to be expressed in spherical coordinates (r, theta and phi) which made the Laplacian look rather fierce. Then the equation was split into 3 variables, each involving one of r, theta or phi. The easiest to solve was the one involving phi which involved only a complex exponential. But periodic nature of the solution made the magnetic quantum number fall out. Pretty good, but nothing earthshaking.

Recursion relations made their appearance with the solution of the radial and the theta equations. So it was plug and chug time with series solutions and recursion relations so things wouldn’t blow up (or as Dr. Gouterman, the instructor, put it: the electron has to be somewhere, so the wavefunction must be zero at infinity). MEGO (My Eyes Glazed Over) until all of a sudden there were the main quantum number (n) and the azimuthal quantum number (l) coming directly out of the recursion relations.

When I first realized what was going on, it really hit me. I can still see the room and the people in it (just as people can remember exactly where they were and what they were doing when they heard about 9/11 or (for the oldsters among you) when Kennedy was shot — I was cutting a physiology class in med school). The realization that what I had considered mathematical diddle, in some way was giving us the quantum numbers and the periodic table, and the shape of orbitals, was a glimpse of incredible and unseen power. For me it was like seeing the face of God.

But what interested me the most about “Lost in Math” was Hossenfelder’s discussion of the different physical laws appearing at different physical scales (e.g. effective laws), emergent properties and reductionism (pp. 44 –> ).  Although things at larger scales (atoms) can be understood in terms of the physics of smaller scales (protons, neutrons, electrons), the details of elementary particle interactions (quarks, gluons, leptons etc.) don’t matter much to the chemist.  The orbits of planets don’t depend on planetary structure, etc. etc.  She notes that reduction of events at one scale to those at a smaller one is not an optional philosophical position to hold, it’s just the way nature is as revealed by experiment.  She notes that you could ‘in principle, derive the theory for large scales from the theory for small scales’ (although I’ve never seen it done) and then she moves on

But the different structures and different laws at different scales is what has always fascinated me about the world in which we exist.  Do we have a model for a world structured this way?

Of course we do.  It’s the computer.

 

Neurologists have always been interested in computers, and computer people have always been interested in the brain — von Neumann wrote “The Computer and the Brain” shortly before his death in 1958.

Back in med school in the 60s people were just figuring out how neurons talked to each other where they met at the synapse.  It was with a certain degree of excitement that we found that information appeared to flow just one way across the synapse (from the PREsynaptic neuron to the POST synaptic neuron).  E.g. just like the vacuum tubes of the earliest computers.  Current (and information) could flow just one way.

The microprocessors based on transistors that a normal person could play with came out in the 70s.  I was naturally interested, as having taken QM I thought I could understand how transistors work.  I knew about energy gaps in atomic spectra, but how in the world a crystal with zillions of atoms and electrons floating around could produce one seemed like a mystery to me, and still does.  It’s an example of ’emergence’ about which more later.

But forgetting all that, it’s fairly easy to see how electrons could flow from a semiconductor with an abundance of them (due to doping) to a semiconductor with a deficit — and have a hard time flowing back.  Again a one way valve, just like our concept of the synapses.

Now of course, we know information can flow the other way in the synapse from POST synaptic to PREsynaptic neuron, some of the main carriers of which are the endogenous marihuana-like substances in your brain — anandamide etc. etc.  — the endocannabinoids.

In 1968 my wife learned how to do assembly language coding with punch cards ones and zeros, the whole bit.  Why?  Because I was scheduled for two years of active duty as an Army doc, a time in which we had half a million men in Vietnam.  She was preparing to be a widow with 2 infants, as the Army sent me a form asking for my preferences in assignment, a form so out of date, that it offered the option of taking my family with me to Vietnam if I’d extend my tour over there to 4 years.  So I sat around drinking Scotch and reading Faulkner waiting to go in.

So when computers became something the general populace could have, I tried to build a mental one using and or and not logical gates and 1s and 0s for high and low voltages. Since I could see how to build the three using transistors (reductionism), I just went one plane higher.  Note, although the gates can be easily reduced to transistors, and transistors to p and n type semiconductors, there is nothing in the laws of semiconductor physics that implies putting them together to form logic gates.  So the higher plane of logic gates is essentially an act of creation.  They do not necessarily arise from transistors.

What I was really interested in was hooking the gates together to form an ALU (arithmetic and logic unit).  I eventually did it, but doing so showed me the necessity of other components of the chip (the clock and in particular the microcode which lies below assembly language instructions).

The next level up, is what my wife was doing — sending assembly language instructions of 1’s and 0’s to the computer, and watching how gates were opened and shut, registers filled and emptied, transforming the 1’s and 0’s in the process.  Again note that there is nothing necessary in the way the gates are hooked together to make them do anything.  The program is at yet another higher level.

Above that are the higher level programs, Basic, C and on up.  Above that hooking computers together to form networks and then the internet with TCP/IP  etc.

While they all can be reduced, there is nothing inherent in the things that they are reduced to which implies their existence.  Their existence was essentially created by humanity’s collective mind.

Could something be going on in the levels of the world seen in physics.  Here’s what Nobel laureate Robert Laughlin (he of the fractional quantum Hall effect) has to say about it — http://www.pnas.org/content/97/1/28.  Note that this was written before people began taking quantum computers seriously.

“However, it is obvious glancing through this list that the Theory of Everything is not even remotely a theory of every thing (2). We know this equation is correct because it has been solved accurately for small numbers of particles (isolated atoms and small molecules) and found to agree in minute detail with experiment (35). However, it cannot be solved accurately when the number of particles exceeds about 10. No computer existing, or that will ever exist, can break this barrier because it is a catastrophe of dimension. If the amount of computer memory required to represent the quantum wavefunction of one particle is Nthen the amount required to represent the wavefunction of k particles is Nk. It is possible to perform approximate calculations for larger systems, and it is through such calculations that we have learned why atoms have the size they do, why chemical bonds have the length and strength they do, why solid matter has the elastic properties it does, why some things are transparent while others reflect or absorb light (6). With a little more experimental input for guidance it is even possible to predict atomic conformations of small molecules, simple chemical reaction rates, structural phase transitions, ferromagnetism, and sometimes even superconducting transition temperatures (7). But the schemes for approximating are not first-principles deductions but are rather art keyed to experiment, and thus tend to be the least reliable precisely when reliability is most needed, i.e., when experimental information is scarce, the physical behavior has no precedent, and the key questions have not yet been identified. There are many notorious failures of alleged ab initio computation methods, including the phase diagram of liquid 3He and the entire phenomenonology of high-temperature superconductors (810). Predicting protein functionality or the behavior of the human brain from these equations is patently absurd. So the triumph of the reductionism of the Greeks is a pyrrhic victory: We have succeeded in reducing all of ordinary physical behavior to a simple, correct Theory of Everything only to discover that it has revealed exactly nothing about many things of great importance.”

So reductionism doesn’t explain the laws we have at various levels.  They are regularities to be sure, and they describe what is happening, but a description is NOT an explanation, in the same way that Newton’s gravitational law predicts zillions of observations about the real world.     But even  Newton famously said Hypotheses non fingo (Latin for “I feign no hypotheses”) when discussing the action at a distance which his theory of gravity entailed. Actually he thought the idea was crazy. “That Gravity should be innate, inherent and essential to Matter, so that one body may act upon another at a distance thro’ a Vacuum, without the Mediation of any thing else, by and through which their Action and Force may be conveyed from one to another, is to me so great an Absurdity that I believe no Man who has in philosophical Matters a competent Faculty of thinking can ever fall into it”

So are the various physical laws things that are imposed from without, by God only knows what?  The computer with its various levels of phenomena certainly was consciously constructed.

Is what I’ve just written a creation myth or is there something to it?

Catching God’s dice being thrown

Einstein famously said “Quantum theory yields much, but it hardly brings us close to the Old One’s secrets. I, in any case, am convinced He does not play dice with the universe.”  Astronomers have caught the dice being thrown (at least as far as the origin of life is concerned).

This post will contain a lot more background than most, as I expect some readers won’t have much scientific background.  The technically inclined can read the article on which this is based — http://www.pnas.org/content/115/28/7166

To cut to the chase — astronomers have found water, a simple sugar, and a compound containing carbon, hydrogen, oxygen and nitrogen around newly forming stars and planets.  You need no more than these 4 atoms to build the bases making up the DNA of our genes, all our sugars and carbohydrates, and 18 of the 20 amino acids that make up our proteins. Throw in sulfur and you have all 20 amino acids.  Add phosphorus and you have DNA and its cousin RNA (neither has been found around newly forming stars so far).

These are the ingredients of life itself. Here’s a quote from the article — “What I can definitively say is that the ingredients needed to make biogenic molecules like DNA and RNA are found around every forming protostar. They are there at an early stage, incorporating into bodies at least as large as comets, which we know are the building blocks of terrestrial planets. Whether these molecules survive or are delivered at the late stage of planet formation, that’s the part of it we don’t know very well.”

So each newly formed star and planetary system is a throw of God’s/Nature’s/Soulless physics’ dice for the creation of life.

As of 1 July 2018, there are 3,797 confirmed planets around 2,841 stars, with 632 having more than one (Wikipedia).  And that’s just in the stars close enough to us to study.  Our galaxy, the milky way, contains 400,000,000,000.

Current estimates have some 100,000,000,000 galaxies in the universe.  https://www.space.com/25303-how-many-galaxies-are-in-the-universe.html.  That’s a lot tosses for life to arise.

Suppose that some day life is found on one such planet.  Does this invalidate Genesis, the Koran?  Assume that they are the word of God somehow transmitted to man.  If the knowledge we have about astronomy (above), biology etc. etc. were imparted to Jesus, Mohammed, Abraham, Moses — it never would have been believed.  The creator had to start with something plausible.

 

 

Life at 250 Atmospheres pressure 1.8 tons/square inch

Tube worms (actually a form of mollusc) live on the depths of the ocean floor where there is almost no light, and very little oxygen. Just as plants use light energy to remove electrons from water to form oxygen and fix carbon, passing the stolen electrons back to oxygen taxing it though intermediary metabolism, symbiotic bacteria living in the worms remove electrons from hydrogen sulfide (H2S) formed by the hydrothermal vents on the seafloor. . How did the tube worms get this far down? By riding decaying wood down there. [Proc. Natl. Acad. Sci. vol. 114 pp. E3652 – E3658 ’17 ] This is the wooden-steps hypothesis [Distel DL, et al. (2000) Nature 403:725–726] which states that the large chemosynthetic mussels (ship worms) found at deep-sea hydrothermal vents descend from much smaller species associated with sunken wood and other organic deposits, and that the endosymbionts of these progenitors made use of hydrogen sulfide from biogenic sources (e.g., decaying wood) rather than from vent fluids.

At 2500 meters down the water pressure is 3750 pounds per square inch. One can only imagine the changes required in the amino acid sequences of their proteins required so they aren’t denatured or aggregated by such pressure.

The idea that life on planetary moons with subsurface oceans (Ganymede, Europa, Titan, Enceladus) could exist is no longer as fantastic as it initially seemed.

If it be found the implications for our conception of our place in the natural world are enormous.

Why wasn’t this mentioned in Genesis or any known creation myth? Assume for the moment that there actually is a creator who made itself known to our ancestors. If it tried to give Abraham, Gautama Budda, Mohammed et. etc. knowledge of these things, it wouldn’t have been believed. Planets? Planets with moons? Please. A few miracles here and there would be all that would be needed.

How Badly Are Thy Genomes, Oh Humanity

With apologies to Numbers 24:5, “How goodly are thy tents, Oh Jacob” —  a recent paper shows how shockingly error ridden our genomes actually are [ Science vol. 337 pp. 64 – 69 ’12 ].  The authors sequenced roughly three quarters of the genes coding for proteins in some 2,439 people — e.g. 15,585 protein coding genes.  This left 98% of the genome untouched, primarily because we really don’t know what it does or how it does it, despite the fact that it controls, when, where and how much of each protein is made.  So they basically looked at the bricks from which we are built (the proteins) and not the plans (the 98%).

The news is not very good.  The subjects came from two groups: 1,351 Europeans and 1,088 Africans (the latter, because genetic diversity is far higher among Africans as that’s where humanity arose, and where mutations have had the longest time to accumulate).

The news is not very good. First, some background.

Recall that each nucleotide is one of four possibilities (A, T, G, C), and that each 3 nucleotides therefore has 4^3 = 64 possibilities.  61/64 combinations code for amino acids which, since we have only 20 gives a certain redundancy of the famed genetic code.   The other 3 combinations code for no amino acid (usually) and tell the machinery making proteins to stop.  Although crucial to our existence, these are called nonsense codons.

The genetic code is therefore 3fold degenerate (on average).  However, some amino acids are coded for by just 1 combination of 3 nucleotides while others are coded by as many as 6.  So some single nucleotide variants (SNVs) leave the amino acid coded for the same (these are the synonymous SNVs), while others change the amino acid (nonSynonymous SNVs), and possibly protein function.

Ask some one with sickle cell anemia how much trouble just one nonSynonymous SNV can cause — it’s only 1 amino acid out of 147.  Even worse, ask someone with cystic fibrosis where just one of 1,480 amino acids is missing.

Here’s the bad news.  In the population as a whole, they found 500,000 single nucleotide variants (SNVs).  If you’re still not sure what is meant by this, the 5 articles in https://luysii.wordpress.com/category/molecular-biology-survival-guide/ should be all the background you need.

More than 400,000 of the variants were previously unknown.  Also more than 400,000 of them were found either in Africans or Europeans but not both.  If you divide 500,000 by 2,439 you get 205 variants per person.  However, SNVs are far more common than that, and each individual contains an average of 14,000.

Well, how many of the 500,000 or so SNVs they found are nonSynonymous? One would think about 1/3 statistically.  However, They found more than half 292,125/500,000 — nearly 60% — were nonSynonymous.

It gets worse: 6,165 of the nonSynonymous variants are nonSense codons.  This means that the protein coded for by such a gene, terminates prematurely, meaning that it can terminate anywhere.  On average one would expect that half of these nonsense codons result in a protein of less than half the normal length.   This would very likely obliterate whatever function the protein had.

Obviously, they couldn’t test all 500,000 SNVs to see how they affected protein function (and we really only have a decent idea of what half our 20,000 or so proteins are doing).  They had to guess.  They came up with a figure of 2 – 4% of the 14,000 SNVs being functionally significant — That’s 280 – 560 significant mutations per individual.

Clearly, despite the horrible examples of cystic fibrosis and sickle cell anemia above, most of these can’t be doing very much, because these were normal people being studied.

There are all sorts of implications of this work.  One is the subject of a future post — how hard this diversity makes drug discovery.  Another reiterates the Tolstoy theme mentioned earlier about the genetic defects causing schizophrenia and autism — ““Happy families are all alike; every unhappy family is unhappy in its own way”.  Thus beginneth Anna Karenina.

For details please see https://luysii.wordpress.com/2010/04/25/tolstoy-was-right-about-hereditary-diseases-imagine-that/  and  https://luysii.wordpress.com/2010/07/29/tolstoy-rides-again-autism-spectrum-disorder/

A third is that this shows that the 1000 fold expansion of the human population has pretty much obviated much natural selection eliminating these variants.  I’ll leave it to the geneticists to figure out what this means for the eventual survival of the species, as these mutants continue to accumulate.

The paper is fascinating, and sure to change our conception of what a ‘normal’ genome actually is.  Nonetheless, all they did was follow Yogi Berra’s dictum — “You can observe a lot by watching.”   It certainly wasn’t creative or ingenious in any sense.  Sometimes grunt work like this wins the day.  I’ll leave this to Ashutosh to write about its philosophical implications for research.

The meek shall inherit the earth — science now tells us how

Statements like this are all over the Old and New Testament (try Psalms 37, or Matthew 5:5).  Mice are a meek lot, but some are meeker than others.  How do you tell?  You perform the tube test — put two mice at each end of a tube and see which one backs out.  If you test groups of 4 mice this way, you find a linear, transitive hierarchy of social dominance 95% of the time.  For details see [ Science vol. 334 pp. 608 – 609, 693 and 697 ]. The tube test correlated well with several other tests of social dominance.  Transitivity just means that mouse  A dominant over  mouse B and mouse B dominant over mouse C implies that mouse A is dominant over mouse C.  Social dominance is independent of weight, motor skill etc. etc.

So they looked at the way nerve cells in the cerebral cortex of the mice communicate with each other.  They studied a type of  nerve cell (pyramidal neuron) in the fifth layer in of the medial prefrontal cerebral cortex (which has 6 layers).  The pyramidal neurons found in layer V communicate with other parts of the brain.  The dominant mice had more effective communication between these cells than the nondominant ones.

Communication between neurons is accomplished by a specialized structure called a synapse where the processes of two nerve cells come into extremely close contact (200 Angstroms) with each other..  Communication between neuron1 (presynaptic) and neuron2 (postsynaptic) is largely one way.  Different small molecules (neurotransmitters) are released by presynaptic neurons and bind to proteins in the postsynaptic neuron, which alter their conformation on binding and cause cause the neuron to fire.  If this sounds like a drug receptor interaction, well it is.  The drug is glutamic acid, a neurotransmitter, and the receptor protein is something called AMPAR (you don’t want to know what the acronym stands for).

So how did the scientists cause the meek to become strong, and the strong to become meek? They injected viruses into the cortex of the animals.  The viruses either contained more AMPARs, or a defective AMPAR which bound glutamic acid but didn’t do anything.  The viruses were able to get their protein load into the layer five pyramidal neurons.  The meek mice getting more AMPARs (so there was more response in the postsynaptic neuron to glutamic acid) became dominant.  The dominant mice receiving the defective AMPARs became meek.

Now you know how one biblical prophecy will come to pass.  Ain’t science grand?

Would a wiring diagram of the brain help you understand it?

Every budding chemist sits through a statistical mechanics course, in which the insanity and inutility of knowing the position and velocity of each and every of the 10^23 molecules of a mole or so of gas in a container is brought home.  Instead we need to know the average energy of the molecules and the volume they are confined in, to get the pressure and the temperature.

However, people are taking the first approach in an attempt to understand the brain.  They want a ‘wiring diagram’ of the brain. e. g. a list of every neuron and for each neuron a list of the other neurons connected to it, and a third list for each neuron of the neurons it is connected to.  For the non-neuroscientist — the connections are called synapses, and they essentially communicate in one direction only (true to a first approximation but no further as there is strong evidence that communication goes both ways, with one of the ‘other way’ transmitters being endogenous marihuana).  This is why you need the second and third lists.

Clearly a monumental undertaking and one which grows more monumental with the passage of time.  Starting out in the 60s, it was estimated that we had about a billion neurons (no one could possibly count each of them).  This is where the neurological urban myth of the loss of 10,000 neurons each day came from.  For details see https://luysii.wordpress.com/2011/03/13/neurological-urban-legends/.

The latest estimate [ Science vol. 331 p. 708 ’11 ] is that we have 80 billion neurons connected to each other by 150 trillion synapses.  Well, that’s not a mole of synapses but it is a nanoMole of them. People are nonetheless trying to see which areas of the brain are connected to each other to at least get a schematic diagram.

Even if you had the complete wiring diagram, nobody’s brain is strong enough to comprehend it.  I strongly recommend looking at the pictures found in Nature vol. 471 pp. 177 – 182 ’11 to get a sense of the  complexity of the interconnection between neurons and just how many there are.  Figure 2 (p. 179) is particularly revealing showing a 3 dimensional reconstruction using the high resolutions obtainable by the electron microscope.  Stare at figure 2.f. a while and try to figure out what’s going on.  It’s both amazing and humbling.

But even assuming that someone or something could, you still wouldn’t have enough information to figure out how the brain is doing what it clearly is doing.  There are at least 3 reasons.

l. Synapses, to a first approximation, are excitatory (turn on the neuron to which they are attached, making it fire an impulse) or inhibitory (preventing the neuron to which they are attached from firing in response to impulses from other synapses).  A wiring diagram alone won’t tell you this.

2. When I was starting out, the following statement would have seemed impossible.  It is now possible to watch synapses in the living brain of awake animal for extended periods of time.  But we now know that synapses come and go in the brain.  The various papers don’t all agree on just what fraction of synapses last more than a few months, but it’s early times.  Here are a few references [ Neuron vol. 69 pp. 1039 – 1041 ’11, ibid vol. 49 pp. 780 – 783, 877 – 887 ’06 ].  So the wiring diagram would have to be updated constantly.

3. Not all communication between neurons occurs at synapses.  Certain neurotransmitters are generally released into the higher brain elements (cerebral cortex) where they bathe neurons and affecting their activity without any synapses for them (it’s called volume neurotransmission)  Their importance in psychiatry and drug addiction is unparalleled.  Examples of such volume transmitters include serotonin, dopamine and norepinephrine.  Drugs of abuse affecting their action include cocaine, amphetamine.  Drugs treating psychiatric disease affecting them include the antipsychotics, the antidepressants and probably the antimanics.

Statistical mechanics works because one molecule is pretty much like another. This certainly isn’t true for neurons. Have a look at http://faculties.sbu.ac.ir/~rajabi/Histo-labo-photos_files/kora-b-p-03-l.jpg.  This is of the cerebral cortex — neurons are fairly creepy looking things, and no two shown are carbon copies.

The mere existence of 80 billion neurons and their 150 trillion connections (if the numbers are in fact correct) poses a series of puzzles.  There is simply no way that the 3.2 billion nucleotides of out genome can code for each and every neuron, each and every synapse.  The construction of the brain from the fertilized egg must be in some sense statistical.  Remarkable that it happens at all.  Embryologists are intensively working on how this happens — thousands of papers on the subject appear each year.

As my brain slowly recovers (or at least gets used to)  from the chemical assault on it by inhaled corticosteroids and muscarinic anticholinergic drugs, I’m having a lot of fun reading a book by Melanie Mitchell “Complexity: A Guided Tour” — but her view of neurons is simplistic in the extreme — hopefully that will improve in the last 100 pages.  A book review will follow.  The whole book is quite relevant to the question — just what would you accept as an explanation of how the brain does what it does?  The question leads into some deep philosophic minefields, but they can’t be avoided.  That’s for another time.

Hopefully, I’ll be able to get back to Anslyn and Dougherty in the coming week (after taxes).