Now is the winter of our discontent

One of the problems with being over 80 is that you watch your friends get sick.  In the past month, one classmate developed ALS and another has cardiac amyloidosis complete with implantable defibrillator.  The 40 year old daughter of a friend who we watched since infancy has serious breast cancer and is undergoing surgery radiation and chemo.  While I don’t have survivor’s guilt (yet), it isn’t fun.

Reading and thinking about molecular biology has been a form of psychotherapy for me (for why, see the reprint of an old post on this point at the end).

Consider ALS (Amyotrophic Lateral Sclerosis, Lou Gehrig disease).  What needs explaining is not why my classmate got it, but why we all don’t have it.  As you know human neurons don’t replace themselves (forget the work in animals — it doesn’t apply to us).  Just think what the neurons  which die in ALS have to do.  They have to send a single axon several feet (not nanoMeters, microMeters, milliMeters — but the better part of a meter) from their cell bodies in the spinal cord to the muscle the innervate (which could be in your foot).

Supplying the end of the axon with proteins and other molecules by simple diffusion would never work.  So molecular highways (called microtubules) inside the axon are constructed, along which trucks (molecular motors such as kinesin and dynein) drag cargos of proteins, and mRNAs to make more proteins.

We know a lot about microtubules, and Cell vol. 179 pp. 909 – 922 ’19 gives incredible detail about them (even better with lots of great pictures).  Start with the basic building block — the tubulin heterodimer — about 40 Angstroms wide and 80 Angstroms high.  The repeating unit of the microtubule is 960 Angstroms long, so 12 heterodimers are lined up end to end in each repeating unit — this is the protofilament of the microtubule, and our microtubules have 13 of them, so that’s 156 heterodimers per microtubule repeat length which is 960 Angstroms or 96 nanoMeters (96 billionths of a meter).  So a microtubule (or a bunch of microtubules extending a meter has 10^7 such repeats or about 1 billion heterodimers.  But the axon of a motor neuron has a bunch of microtubules in it (between 10 and 100), so the motor neuron firing to  the muscle moving my finger has probably made billions and billions of heterodimers.  Moreover it’s been doing this for 80 plus years.

This is why, what needs explaining is not ALS, but why we don’t all have it.

Here’s the old post

The Solace of Molecular Biology

Neurology is fascinating because it deals with illnesses affecting what makes us human. Unfortunately for nearly all of my medical career in neurology ’62 – ’00 neurologic therapy was lousy and death was no stranger. In a coverage group with 4 other neurologists taking weekend call (we covered our own practices during the week) about 1/4 of the patients seen on call weekend #1 had died by on call weekend #2 five weeks later.

Most of the deaths were in the elderly with strokes, tumors, cancer etc, but not all. I also ran a muscular dystrophy clinic and one of the hardest cases I saw was an infant with Werdnig Hoffman disease — similar to what Steven Hawking has, but much, much faster — she died at 1 year. Initially, I found the suffering of such patients and their families impossible to accept or understand, particularly when they affected the young, or even young adults in the graduate student age.

As noted earlier, I started med school in ’62, a time when the genetic code was first being cracked, and with the background then that many of you have presently understanding molecular biology as it was being unravelled wasn’t difficult. Usually when you know something you tend to regard it as simple or unimpressive. Not so the cell and life. The more you know, the more impressive it becomes.

Think of the 3.2 gigaBases of DNA in each cell. At 3 or so Angstroms aromatic ring thickness — this comes out to a meter or so stretched out — but it isn’t, rather compressed so it fits into a nucleus 5 – 10 millionths of a meter in diameter. Then since DNA is a helix with one complete turn every 10 bases, the genome in each cell contains 320,000,000 twists which must be unwound to copy it into RNA. The machinery which copies it into messenger RNA (RNA polymerase II) is huge — but the fun doesn’t stop there — in the eukaryotic cell to turn on a gene at the right time something called the mediator complex must bind to another site in the DNA and the RNA polymerase — the whole mess contains over 100 proteins and has a molecular mass of over 2 megaDaltons (with our friend carbon containing only 12 Daltons). This monster must somehow find and unwind just the right stretch of DNA in the extremely cramped confines of the nucleus. That’s just transcription of DNA into RNA. Translation of the messenger RNA (mRNA) into protein involves another monster — the ribosome. Most of our mRNA must be processed lopping out irrelevant pieces before it gets out to the cytoplasm — this calls for the spliceosome — a complex of over 100 proteins plus some RNAs — a completely different molecular machine with a mass in the megaDaltons. There’s tons more that we know now, equally complex.

So what.

Gradually I came to realize that what needs explaining is not the poor child dying of Werdnig Hoffman disease but that we exist at all and for fairly prolonged periods of time and in relatively good shape (like my father who was actively engaged in the law and a mortgage operation until 6 months before his death at age100). Such is the solace of molecular biology. It ain’t much, but it’s all I’ve got (the religious have a lot more). You guys have the chemical background and the intellectual horsepower to understand molecular biology — and even perhaps to extend it.

 

The Russian language

“The power of language is its ambiguity” sayeth I.  This came up because my nephew married a wonderful Russian expat a few weeks ago.  Plucky fellow that he is, he’s learning to speak Russian.  Like my wife’s friend of 50+ years ago he is amazed at how many words the language has.  Russian apparently has a word for everything so there is little ambiguity, which must make the language hard to pun in.

Someone Googled the number of words in Russian and English and they’re about the same.

Perhaps the lack of ambiguity makes Russian hard to learn (and use).  Computer languages (basic, C, pascal) are completely unambiguous.  Every reserved word and operator means exactly one thing, no more no less.

Most people find programming far from intuitive.  It’s hard to express our sloppy ideas in unambiguous computer language.  Given it’s difficulty giving concrete form to your ideas, computer languages aren’t as powerful (in the sense of being easy to use) as your sloppy sentences.

Why should language be so ambiguous?  My guess is, that it has to be this way given the way we perceive the world (and the way the world probably actually is — ontology if you want to impress your friends).

We don’t live in Plato’s world of perfect forms, but in a world of objects that only partially and rather poorly instantiate them.  This is as true of science as anything else — even supposedly well defined terms change their meaning — are the giant viruses really viruses?  What do we really mean by a gene?  It used to be a part of DNA coding for a protein, but what about the DNA that controls when and where a protein is made.   Mutations here can cause disease, so are they genes?

Language, to be useful, must express our imperfect ways of rigidly classifying the world (perhaps because such a classification is impossible).

Socially, I never thought of our family as inhibited, but the Russians I met seemed more alive and vibrant than our lot (this without them living up to their reputation of hard drinking).

Prolegomena to reading Fall by Neal Stephenson

As a college freshman I spent hours trying to untangle Kant’s sentences in “Prolegomena to Any Future Metaphysics”  Here’s sentence #1.   “In order that metaphysics might, as science, be able to lay claim, not merely to deceitful persuasion, but to insight and conviction, a critique of reason itself must set forth the entire stock of a priori concepts, their division according to the different sources (sensibility, understanding, and reason), further, a complete table of those concepts, and the analysis of all of them along with everything that can be derived from that analysis; and then, especially, such a critique must set forth the possibility of synthetic cognition a priori through a deduction of these concepts, it must set forth the principles of their use, and finally also the boundaries of that use; and all of this in a complete system.”

This post is something to read before tackling “Fall” by Neal Stephenson, a prolegomena if you will.  Hopefully it will be more comprehensible than Kant.   I’m only up to p. 83 of a nearly 900 page book.  But so far the book’s premise seems to be that if you knew each and every connection (synapse) between every neuron, you could resurrect the consciousness of an individual (e.g. a wiring diagram).  Perhaps Stephenson will get more sophisticated as I proceed through the book.  Perhaps not.  But he’s clearly done a fair amount neuroscience homework.

So read the following old post about why a wiring diagram of the brain isn’t enough to explain how it works.   Perhaps he’ll bring in the following points later in the book.

Here’s the old post.  Some serious (and counterintuitive) scientific results to follow in tomorrow’s post.

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.

 

Feynman and Darwin

What do Richard Feynman and Charles Darwin have in common?  Both have written books which show a brilliant mind at work.  I’ve started reading the New Millennium Edition of Feynman’s Lectures on Physics (which is the edition you should get as all 1165 errata found over the years have been corrected), and like Darwin his thought processes and their power are laid out for all to see.  Feynman’s books are far from F = ma.  They are basically polished versions of lectures, so it reads as if Feynman is directly talking to you.  Example: “We have already discussed the difference between knowing the rules of the game of chess and being able to play.”  Another: talking about Zeno  “The Greeks were somewhat confused by such problems, being helped, of course, by some very confusing Greeks.”

He’s always thinking about the larger implications of what we know.  Example: “Newton’s law has the peculiar property that if it is right on a certain small scale, then it will be right on a larger scale”

He then takes this idea and runs with it.  “Newton’s laws are the ‘tail end’ of the atomic laws extrapolated to a very large size”  The fact that they are extrapolatable and the fact that way down below are the atoms producing them means, that extrapolatable laws are the only type of physical law which could be discovered by us (until we could get down to the atomic level).  Marvelous.  Then he notes that the fundamental atomic laws (e.g. quantum mechanics) are NOTHING like what we see in the large scale environment in which we live.

If you like this sort of thing, you’ll love the books.  I don’t think they would be a good way to learn physics for the first time however.  No problems, etc. etc.  But once you’ve had exposure to some physics “it is good to sit at the feet of the master” — Bill Gates.

Most of the readership is probably fully engaged with work, family career and doesn’t have time to actually read “The Origin of Species”. In retirement, I did,and the power of Darwin’s mind is simply staggering. He did so much with what little information he had. There was no clear idea of how heredity worked and at several points he’s a Lamarckian — inheritance of acquired characteristics. If you do have the time I suggest that you read the 1859 book chapter by chapter along with a very interesting book — Darwin’s Ghost by Steve Jones (published in 1999) which update’s Darwin’s book to contemporary thinking chapter by chapter.  Despite the advances in knowledge in 140 years, Darwin’s thinking beats Jones hands down chapter by chapter.

What can dogs tell us about cancer, and (wait for it) sexually transmitted disease

What can 546 dogs tell us about cancer, and STDs (sexually transmitted diseases)?  An enormous amount ! [ Science vol 365 pp. 440 – 441, 464 3aau9923 1 –> 7 ’19 ].  You may have heard about the transmissible tumor that has reduced the Tasmanian Devil population from its appearance in ’96 by 80%.  The animals bite each other transmitting the tumor.  Only 10 – 100 cells are transferred, but death occurs within a year.  The cells survive because Tasmanian devels have low genetic diversity.

The work concerns a much older transmissible tumor (Canine Transmissible Venereal Tumor — aka CTVT) which appeared in Asia an estimated 6,000 year ago, and began dispersing worldwide 2,000 years ago.   Unlike the Tasmanian devil tumor, the tumor is usually cleared by the immune system.

The Science paper has 80+ authors from all over the world, who sequenced the protein coding part of the dog genome (the exome) to a > 100fold depth.   The exome contains 43.6 megabases.   The tumor is transmitted by sex, and the authors note that this mode of transmission nearly requires a rather indolent clinical course, as the animal must survive long enough to transmit the organism again.  This fits with syphilis, AIDs, gonorrhea.  Contrast this with anthrax, cholera, plague which spread differently and kill much faster.

So what does CTVT tell us about cancer?   Quite a bit.  First some background.  The Cancer Genome Atlas (CGA) was criticized as being a boondoggle, but it at least gave us an idea of how many mutations are present in various cancers– around 100 in colon and breast cancers.

Viewed across all dogs, the CTVT genome is riddled with somatic mutations (as compared to the genome of the dog carrying the tumor) –148,030 single nucleotide variants (3.4/1000 !) 12,177 insertion/deletions.  Of the 20,000 dog genes only 2,000 didn’t contain a mutation.   This implies that most genes in the mammalian genome aren’t needed by the cancer cells.  The CTVTs also show no signs of the high rates of chromosomal instability seen in human tumors.

The work provides evidence that cancer isn’t inherently progressive.  This gives hope that some relatively indolent human cancers (say cancer of the prostate) can be controlled.  This calls for ‘adaptive therapy’  — something that limits tumor  growth rather than trying to kill every cancer cell with curative therapy which, if it fails, essentially selects for more aggressive cancer cells.

Some 14,412 genes have 1 mutation changing the amino acid sequence (nonSynonymous) and 5,704 have protein truncating mutations.  The ratio of synonymous to non synonymous mutations is about 3 implying that the mutations which have arisen haven’t been selected for (after all the triplet code for 20 amino acids and 1 stop codon has 64 possibilities), so the average amino acid has 3 codons for it.  This is called neutral genetic drift.

They also found 5 mutated genes present in all 541 tumors — these are the driver mutations, 3 are well known, MYC, PTEN, and retinoblastoma1.

Tons to think about here.  I’ll be away for a few weeks traveling and playing music, but this work should keep you busy thinking about its implications.

 

 

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.

Babies are smarter than we thought

In a great study from France some 150 5 month old infants were shown to be able to associate an abstract 3 syllable pattern with an image and react when the pattern wasn’t consonant with images they’d been shown many times before [ Proc. Natl. Acad. Sci. vol. 116 pp. 5805-5810 ’19 ].

Well, the kids weren’t geniuses and talking.  So how could the researchers make such a statement?  The babies were sitting in their parents laps with a high density (120 electrode) EEG cap on their heads.  They were exposed to monosyllable triplets in various patterns AAB, ABA, ABB, BBA etc. Following  each triplet presentation a picture of a fish or a lion was shown.

For example,  for most of the time they experienced AAB lion AAB lion AAB lion —but occasionally AAB fish was thrown in.  The EEG was quite different with the fish.

Even better, they exposed the child to the picture (lion) first followed by the trisyllable.  If the trisyllable was AAB there was no reaction, but it if was ABA there was a reaction implying that the babies had linked the picture and the sound pattern.

This is excellent evidence for the ability of 5 month old infants to associate an abstract (sound) pattern with an unrelated visual stimulus.

They did many more experiments but you get the idea.

You’d better. The infants did.

It would be fascinating to repeat the experiment with chimpanzees.

Measuring what the brain thinks it is perceiving rather than the stimulus itelf

It’s usually not hard to do neuropsychology experiments.  The hard part is being smart enough to think of a good one.  I found a recent one absolutely brilliant, as the authors were able to measure a signal which had to be coming from the conscious perception of motion in a particular direction [ Proc. Natl. Acad. Sci. vol. 116 pp. 5096 – 5101 ’19 ].

Throw any stimulus at a living human and you’ll get some sort of measurable electrical response or a measurable change in blood flow in a particular brain area (you can use functional MRI — fMRI to measure the latter).  But how do you know whether the response has anything to do with conscious perception.  You don’t.

Here’s where the cleverness of the authors comes in.  Probably most people reading this post know about Cartesian coordinates, but to not leave the nonMathematically inclined behind, I’ll use baseball to describe the experimental set up.

We talk about a baseball diamond, and that’s the way it looks to people sitting in the stands behind home plate.  But actually the 4 bases form a perfect square 90 feet on a side.

So turn the ‘diamond’ on its side so the path between home plate and first base is horizontal, as is the path between 2nd and third while the paths between first and second and between third base and home are vertical.

Now that you’re oriented, imagine this on a computer screen. What the authors did was to light up first and third for .15 seconds, turn things off for .067 seconds and then light up home plate and second base for .15 seconds.  So the dot pairs alternate about 4 times a second.

But what does this look like to a human being?  For about 10 seconds the dots actually appear to actually be moving horizontally, then they appear to be moving vertically.  Remember the dots themselves  aren’t moving at all, just blinking.

The brilliance of the setup is that with exactly the same stimulus (alternately lit pairs of dots) the same person will have two different perceptions of the way the dots are moving at different times.

What do you think they did next?

They put the same people in an MRI machine and then showed the dots actually moving across the screen horizontally and then vertically.  Different parts of the brain responded to vertical motion than responded to horizontal motion.  The response was increased blood flow to that area, which is what fMRI actually measures.

So then back to the original set up with alternate pairs of dots on and off about 4 times a second.  Then they asked people which way the dots appeared to be moving, and the area of the brain which lit up (showed increased flow) was the same one which lit up to actual motion in that direction.

So they were actually measuring conscious perception of motion, rather than some nonspecific response to the visual stimulus, because the stimulus didn’t change regardless of the way it was perceived.

One of things this means is that the brain is producing the same neural response when it perceives motion in one direction (even though none is present) that real motion produces.

I think this is just brilliant.  Bravo. Something for the philosophers among you to chew on.

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”

Book recommendation

“It’s complicated”.  No this isn’t about the movie with Meryl Streep but the response I got from several Harvard PhD physicists five years ago at Graduate Alumni Day in April 2014.  A month earlier the BICEP2 experiment claimed to have seen B-mode polarization in the cosmic background radiation, which would have been observational proof of cosmic inflation.  Nobel prize material for sure.  Unfortunately the signal turned out to be from dust in our galaxy, the milky way

You can read all about it in “Losing the Nobel Prize” by Brian Keating, who developed the instrumentation for BICEP2.  I recommend the book for several reasons.  The main reason is the discussion of cosmology and its various theories starting with Galileo (p. 28) getting up to  the B-Modes that BICEPs thought it saw by p. 138.  The discussion is incredibly clear, with discussions (to name a few) of how Galileo knew Ptolemy was wrong (the way the moons of Jupiter moved around it in time), refracting vs.reflecting telescopes, Hubble and cepheid variables, Vera Rubin and why she didn’t get a Nobel — she died too soon, how polaroid glasses work, and why bouncing of water is enough to polarize unpolarized light.  Want more? Fred Hoyle and steady state cosmology, the problems with the big bang (smoothness problem, horizon problem, flatness problem) solved by Alan Guth and inflation, false vacuum, and finally what B-modes actually are.

If you’ve a typical reader of blogs scientific but not a pro in physics, astronomy, cosmology, you’ve probably heard all these terms. Keating explains them clearly.

Even better, he writes well and is funny.  Here is the opening paragraph of the book.

“Each year, on December tenth, thousands of worshippers convene in Scandinavia to commemorate the passing of an arms dealer known as the merchant of death.  The eschatological ritual features all the rites and incantations befitting a pharaoh’s funeral.  Haunting dirges play as the worshippers, bedecked in mandatory regalia, mourn the merchant.  He is eerily present; his visage looms over the congregants as they feast on exotic game, surrounded by fresh-cut flowers imported from the merchant’s mausoleum.  The event culminates with the presentation of gilded, graven images bearing his likeness.”

Anything dealing with the creation of the universe has theological overtones, and we can regard the book as a history of various scientific creation myths, the difference being that they are abandoned when evidence is found which contradicts them.  Georges’ Lemaitre, a catholic priest and relativist puts in more than an appearance (p. 56) as he predicted what is probably the first big bang theory — the primeval atom with its subsequent expansion.

The book isn’t all science, and the author whose Jewish father abandoned them was raised by a catholic step-father describes being an altar boy for a time.   Then there are adventure stories of journeys to the south pole for the BICEP experiment.

There’s a lot more in the book, which is definitely worth a read.

Finally a few personal notes.  The man who brought BICEP2 down to earth David Spergel appears.  He’s a good guy.  At my 50th reunion there my wife and I  were standing in our reunion suits outside our hotel across route 1 waiting for a bus to take us across.  Some guy (Spergel) sees us an offers a ride to campus. On the ride over I asked what he did, and he says astronomy and physics.  So I asked how come the universe is said to be homogenous when all we see is clumpy galaxies and stars — you asked the right guy saith Spergel, and he launches into an explanation (which I’ve forgotten).  I mention that Jim Hartle is a class member.  “He’s very smart” saith David.  Later I tell Hartle the same story.  “He’s very smart” saith Jim.

Another good person is Meryl Streep.  A cousin is in movies both acting in the past and now directing and knows her.  Her father was a great admirer, so Meryl took the trouble to hike over to New Jersey and say hello.  She didn’t have to do that.  Unfortunately in the movie mentioned first, Meryl had to play a porn star with her aged scrawny body (probably Harvey Weinstein put her up to it).  I couldn’t stand it and walked out at that point.