Tag Archives: Cartesian dualism

Chemistry and Biochemistry can’t answer the important questions but without them we are lost

The last two posts — one concerning the histone code and cerebral embryogenesis https://luysii.wordpress.com/2018/06/07/omar-khayyam-and-the-embryology-of-the-cerebral-cortex/ and the other concerning PVT1 enhancers promoters and cancer https://luysii.wordpress.com/2018/06/04/marshall-mcluhan-rides-again/ — would be impossible without chemical and biochemical knowledge and technology, but the results they produce and the answers they seek and lie totally outside both disciplines.

In fact they belong outside the physical realm in the space of logic, ideas, function — e.g. in the other half of the Cartesian dichotomy — the realm of ideas and spirit.  Certainly the biological issues are instantiated physically in molecules, just as computer memory used to be instantiated in magnetic cores, rather than transistors.

Back when I was starting out as a grad student in Chemistry in the early 60s, people were actually discovering the genetic code, poly U coded for phenylalanine etc. etc.  Our view was that all we had to do was determine the structure of things and understanding would follow.  The first xray structures of proteins (myoglobin) and Anfinsen’s result on ribonuclease showing that it could fold into its final compact form all by itself reinforced this. It also led us to think that all proteins had ‘a’ structure.

This led to people thinking that the only difference between us and a chimpanzee were a few amino acid differences in our proteins (remember the slogan that we were 98% chimpanzee).

So without chemistry and biochemistry we’d be lost, but the days of crude reductionism of the 60s and 70s are gone forever.  Here’s another example of chemical and biochemical impotence from an earlier post.

The limits of chemical reductionism

“Everything in chemistry turns blue or explodes”, so sayeth a philosophy major roommate years ago.  Chemists are used to being crapped on, because it starts so early and never lets up.  However, knowing a lot of organic chemistry and molecular biology allows you to see very clearly one answer to a serious philosophical question — when and where does scientific reductionism fail?

Early on, physicists said that quantum mechanics explains all of chemistry.  Well it does explain why atoms have orbitals, and it does give a few hints as to the nature of the chemical bond between simple atoms, but no one can solve the equations exactly for systems of chemical interest.  Approximate the solution, yes, but this his hardly a pure reduction of chemistry to physics.  So we’ve failed to reduce chemistry to physics because the equations of quantum mechanics are so hard to solve, but this is hardly a failure of reductionism.

The last post “The death of the synonymous codon – II” puts you exactly at the nidus of the failure of chemical reductionism to bag the biggest prey of all, an understanding of the living cell and with it of life itself.  We know the chemistry of nucleotides, Watson-Crick base pairing, and enzyme kinetics quite well.  We understand why less transfer RNA for a particular codon would mean slower protein synthesis.  Chemists understand what a protein conformation is, although we can’t predict it 100% of the time from the amino acid sequence.  So we do understand exactly why the same amino acid sequence using different codons would result in slower synthesis of gamma actin than beta actin, and why the slower synthesis would allow a more leisurely exploration of conformational space allowing gamma actin to find a conformation which would be modified by linking it to another protein (ubiquitin) leading to its destruction.  Not bad.  Not bad at all.

Now ask yourself, why the cell would want to have less gamma actin around than beta actin.  There is no conceivable explanation for this in terms of chemistry.  A better understanding of protein structure won’t give it to you.  Certainly, beta and gamma actin differ slightly in amino acid sequence (4/375) so their structure won’t be exactly the same.  Studying this till the cows come home won’t answer the question, as it’s on an entirely different level than chemistry.

Cellular and organismal molecular biology is full of questions like that, but gamma and beta actin are the closest chemists have come to explaining the disparity in the abundance of two closely related proteins on a purely chemical basis.

So there you have it.  Physicality has gone as far as it can go in explaining the mechanism of the effect, but has nothing to say whatsoever about why the effect is present.  It’s the Cartesian dualism between physicality and the realm of ideas, and you’ve just seen the junction between the two live and in color, happening right now in just about every cell inside you.  So the effect is not some trivial toy model someone made up.

Whether philosophers have the intellectual cojones to master all this chemistry and molecular biology is unclear.  Probably no one has tried (please correct me if I’m wrong).  They are certainly capable of mounting intellectual effort — they write book after book about Godel’s proof and the mathematical logic behind it. My guess is that they are attracted to such things because logic and math are so definitive, general and nonparticular.

Chemistry and molecular biology aren’t general this way.  We study a very arbitrary collection of molecules, which must simply be learned and dealt with. Amino acids are of one chirality. The alpha helix turns one way and not the other.  Our bodies use 20 particular amino acids not any of the zillions of possible amino acids chemists can make.  This sort of thing may turn off the philosophical mind which has a taste for the abstract and general (at least my roommates majoring in it were this way).

If you’re interested in how far reductionism can take us  have a look at http://wavefunction.fieldofscience.com/2011/04/dirac-bernstein-weinberg-and.html

Were my two philosopher roommates still alive, they might come up with something like “That’s how it works in practice, but how does it work in theory? 

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It ain’t the bricks, it’s the plan

Nothing better shows the utility (and the futility) of chemistry in biology than using it to explain the difference between man and chimpanzee. You’ve all heard that our proteins are only 2% different than the chimp, so we are 98% chimpanzee. The facts are correct, the interpretation wrong. We are far more than the protein ‘bricks’ that make us up, and two current papers in Cell [ vol. 163 pp. 24 – 26, 66 – 83 ’15 ] essentially prove this.

This is like saying Monticello and Independence Hall are just the same because they’re both made out of bricks. One could chemically identify Monticello bricks as coming from the Virginia piedmont, and Independence Hall bricks coming from the red clay of New Jersey, but the real difference between the buildings is the plan.

It’s not the proteins, but where and when and how much of them are made. The control for this (plan if you will) lies outside the genes for the proteins themselves, in the rest of the genome (remember only 2% of the genome codes for the amino acids making up our 20,000 or so protein genes). The control elements have as much right to be called genes, as the parts of the genome coding for amino acids. Granted, it’s easier to study genes coding for proteins, because we’ve identified them and know so much about them. It’s like the drunk looking for his keys under the lamppost because that’s where the light is.

We are far more than the protein ‘bricks’ that make us up, and two current papers in Cell [ vol. 163 pp. 24 – 26, 66 – 83 ’15 ] essentially prove this.

All the molecular biology you need to understand what follows is in the following post — https://luysii.wordpress.com/2010/07/07/molecular-biology-survival-guide-for-chemists-i-dna-and-protein-coding-gene-structure/

Briefly an enhancer is a stretch of DNA distinct from the DNA coding for a given protein, to which a variety of other proteins called transcription factors bind. The enhancer DNA and associated transcription factors, then loops over to the protein coding gene and ‘turns it on’ — e.g. causes a huge (megaDalton) enzyme called pol II to make an RNA copy of the gene (called mRNA) which is then translated into protein by another huge megaDalton machine called the ribosome. Complicated no? Well, it’s happening inside you right now.

The faces of chimps and people are quite different (but not so much so that they look frighteningly human). The cell paper studied cells which in embryos go to make up the bones and soft tissues of the face called Cranial Neural Crest Cells (CNCCs). How did they get them? Not from Planned Parenthood, rather they made iPSCs (induced Pluripotent Stem Cells — https://en.wikipedia.org/wiki/Induced_pluripotent_stem_cell) differentiate into CNCCs. Not only that but they studied both human and chimp CNCCs. So you must at least wonder how close to biologic reality this system actually is.

It’s rather technical, but they had several ways of seeing if a given enhancer was active or not. By active I mean engaged in turning on a given protein coding gene so more of that protein is made. For the cognoscenti, these methods included (1) p300 binding (2) chromatin accessibility,(3) H3K4Me1/K3K4me3 ratio, (4) H3K27Ac.

The genome is big — some 3,200,000,000 positions (nucleotides) linearly arranged along our chromosomes. Enhancers range in size from 50 to 1,500 nucleotides, and the study found a mere 14,500 enhancers in the CNCCs. More interestingly 13% of them were activated differentially in man and chimp CNCCs. This is probably why we look different than chimps. So although the proteins are the same, the timing of their synthesis is different.

At long last, molecular biology is beginning to study the plan rather than the bricks.

Chemistry has a great role in this and will continue to do so. For instance, enhancers can be sequenced to see how different enhancer DNA is between man and chimp. The answer is not much (again 2 or so nucleotides per hundred nucleotides of enhancer). The authors did find one new enhancer motif, not seen previously called the coordinator motif. But it was present in man in chimp. Chemistry can and should explain why changing so few nucleotides changes the proteins binding to a given enhancer sequence, and it will be important in designing proteins to take advantage of these changes.

So why is chemistry futile? Because as soon as you ask what an enhancer or a protein is for, you’ve left physicality entirely and entered the realm of ideas. Asking what something is for is an entirely different question than how something actually does what it is for.  The latter question  is answerable by chemistry and physics. The first question is unanswerable by them.  The Cartesian dualism of flesh and spirit is alive and well.

It’s interesting to see how quickly questions in biology lead to teleology.