#79. Scientific Brainstorming Methods Used Here

Red, theory; black, fact

The observer in an improvised eclipse observatory

Explanations of the scientific method all have a spongy spot: “Think of a theory.” So how do you do that? The most advanced form of the scientific method, strong inference, is even worse: “Think of at least two theories to account for the same facts!” Here I am trying to bring some system to the task.

Some of these methods (A list) reflect the structure of nature (the transmitter); others (B list) reflect the limitations of the human brain (the receiver). The hope is that all this can be condensed and codified somewhat, possibly using information theory. Each method is followed by the number of at least one post in which it was used.

A. Nature (Encoder? Dictate independent variables of experiments?)

1. Apply consilience. (Mental schematics of how something works that are useful in one field/category can also be useful in a different field/category.) Apply across species boundaries, as when using research on rats to get insights about diseases in humans. #57, #69, #75
2. Consilience: apply across levels of description. Examples of levels of description are the human world, made of societies, made of individuals, made of cells, made of molecules, made of atoms, made of electrons, protons, and neutrons, made of…? #73, #75
3. Consilience: apply across length scales and timescales. This is basically the usefulness of the Fourier, wavelet, and LaPlace transforms. #12, #13, #23
4. Consilience: apply between nature and technology. Example: the parts of the eye correspond to the parts of a camera. #2, #3, #76
5. Match numbers of things in different fields. Example: there are five main neuromodulators in the human brain and there are five dimensions of personality. #69
6. Identify if-then relationships across levels of description. An example is allosteric control of an enzyme’s catalytic site; the primary, secondary, and tertiary structures of proteins are sub-levels of description. #74, #77
7. Use the evolutionary psychology concept (human behaviour can be directly explained by evolutionary arguments), which is identifying if-then relationships across levels of description and timescales. #15-18, #21, etc.
8. Apply recursion (applying the same process to the result of its previous application). #58
9. Re-use a concept. #62, #67
10. Add feedback. The presence of exponential increases or decreases hints at feedback. #74
11. Add hormesis. (Effects can be either increasing or decreasing in different dose ranges of the same substance.) #The hormesis posts in Experimentalist’s Progress
12. Go for cute. (Assume that a design exists.) #70
13. Generalize. Everyday life can be a source of observations you can generalize into a theory. #12, #67, #73.
14. Visualize. #58
15. Visualize with zooming in. #72

B. Human (Decoder? Dictate dependent variables of experiments?)

1. Apply new concepts published by others. #1
2. Call a spade a spade. Example: chromatin is a polymer and therefore polymer behaviors such as swelling are relevant to cell biology. #66
3. Identify a problem. Problems are the friends of the theoretician. #71
4. Admit variables in stages to a simple core idea (messification). This is more gradual and structured than mind mapping and involves visualization with zooming in. #71, #72, #74, #76
5. Parameterize supposed dichotomies. #75
6. Selectively elevate 1-3 facts in search of an explanatory core. #25, #52, #60, #64
7. Take the next step. You can be sure that Nature has—long ago. #14, #75, #77
8. Contemplate the mathematics. #19, #73
9. Avoid perfectionism. #The early physics posts
10. Ask the 5 Ws questions. #77
11. Reverse the conventional explanation. As an example, combustion adds a substance (oxygen); it doesn’t subtract a substance (phlogiston) as the alchemists believed. #The hormesis posts in Experimentalist’s Progress
12. Take the math constructs literally, not just as aids to calculation. The heliocentric model of the solar system was literally true, in addition to being an aid to calculation as it was first billed. Modern quantum mechanics is full of such aids to calculation but avoids answering the question: “How and of what is the world made?” #71
13. Build a Rube Goldberg device on paper to explain the phenomenon. Some explanation may be more helpful than none. #68, #74

(The research question determines the controlled variables of experiments that are not independent variables.)

[Still to be carefully reviewed to identify potentially new brainstorming methods: posts 29-65, about half the blog.] 

#78. My Thinking on Evolutionary Psychology: Summary to Date

EP

Red, theory; black, fact

Darwin's first diagram of evolution

The behavioral innovations occurring in the evolutionary sequence leading to ourselves may have been, in chronological order:

• H. habilis:  tool manufacturing and gender roles.
• H. erectus: systemic refugee production, dispersal, ethnicity, and language.
• Early H. sapiens: warfare, shelter building, and tricksterism.
• Late H. sapiens: siege resistance and religion.

General hypotheses: 1) The earlier the innovation, the less modifiable it will be; 2) The dominant neuromodulators that organize the innovations emerging post-H. habilis will be noradrenalin (primordial organizer of responses to intraspecific competition) and serotonin (primordial organizer of responses to predation). 3)  Siege resistance is the adaptive form of the corresponding failure mode siege mentality.

Picture credit: Wiki Commons

#77. The Anorthosite Problem [chemistry]

CH

Red, theory; black, fact

Labradorite facade on Bank Street, Ottawa, ON

The “anorthosite problem” is a problem in geology. Anorthosite is a rock made mostly of a calcium-rich type of feldspar. Labradorite is a well-known example. The moon rocks from the lunar highlands are anorthosites. 

Existing Theory

When a magma chamber far below the surface cools and solidifies into rock, it does so very slowly because of the insulation provided by the overlying rocks. Slow cooling leads to big mineral grains in the eventual rock because each grain is a crystal of some mineral, and there is plenty of time for crystal growth.

As the temperature slowly falls, one type of mineral after another comes out of the magma, in a fixed sequence. The iron-rich minerals fall to the bottom of the chamber and collect there, while the calcium and sodium types of feldspar float to the top of the chamber and collect there. 

Anyway, that’s the theory. It predicts that anorthosites will be underlain by iron-rich rocks like gabbro, peridotite, amphibolite, and serpentinite, some of which are called greenstones.

The problem is that immense deposits of anorthosite are not found in association with any iron-rich rocks. 

My Emphasis

Interestingly, the biggest of these anorthosite deposits are the oldest, dating from the Archean and Proterozoic eras of geological history.  And thereon, I believe, hangs a tale.

Radioactive isotopes can be expected to have been much more abundant in the distant past than now if we extrapolate their exponential decay curves backwards in time to those eras. 

Moreover, all the natural radioactive elements are incompatible with the crystal lattices of the main rock-forming minerals crystallizing around when anorthosite does. Therefore, they will stay in the melt and get concentrated there as the rock-formers leave. The energy of their radiation will be converted into additional heat in the dense magma before the radiation can escape. 

My Solution

Therefore, the radioactive self-heating of the residual magma will become progressively stronger until the cooling process almost stalls, leading to a long-lasting plateau in the cooling curve of the magma.

During the plateau, which may actually be a second and slower exponential, the loss of the iron-rich minerals has time to run to completion, resulting in a large magma emplacement that forms only granite, a low-iron rock. The iron-rich greenstones will be under that, and nowhere near the anorthosite at the very top. This is the sequence we actually observe.

Therefore, the early anorthosite deposits, however massive, will have no iron-rich rocks in sight.

QED.

P.S. The crystals forming during the plateau phase will be notably large due to the especially slow cooling. This may be the origin of the large crystals categorized as phenocrysts.

#76. Next Niche [evolution]

EV

Red, theory; black, fact

Safdie’s Habitat 67 in Montreal 

In terms of our evolution, where did Homo sapiens come from and where are we going? The fossil evidence shows that we evolved from a wandering big-game hunter called Homo erectus. Where are we going? What shall be our next ecological niche? 

Reef former.

Examples of reef formers are the species of coral polyp that built the Great Barrier Reef in Australia. Think of such a structure transposed to a land environment and covered in solar panels like the leaves on a tree, and that, I think, is our distant future. The overall form would be designed to maximize the sum of wind and solar energy harvested per year.

Multiple works of science fiction have predicted something like this, such as Asimov’s pre-collapse Trantor, or the world of JG Ballard’s “Build-Up.” 

However, a reef does not cover an entire planet as in those imaginings, only those places where all its necessities of life are available. The non-reef-forming descendants of H. sapiens would occupy some or all of the remaining land area.

Photo by philippe collard on Unsplash

#75. The Broad Context of Religion [evolutionary psychology]

EP

Red, theory; black, fact

[Quotes indicate metaphor.]

• Organized religion may have arisen as a counter-adaptation to the anti-invasion adaptations  of a neighbouring, powerful country that included sorties.  For the Abrahamic religions, that powerful but geographically vulnerable country would be ancient Egypt. For the Eastern religions, the powerful but vulnerable neighbor would be ancient China.

• People are "amphibians": each of us has a collectivist part existing in genetic superposition with an individualistic part. In systems that officially celebrate the former, the latter cannot be owned and must be pushed into the Jungian Shadow. And vice versa. In Freudian terms, the unacceptable wishes emerge in disguised form: religion in individual-celebrating systems, and hero worship in collective-celebrating systems.

• The longstanding debate in philosophy between rationalism and empiricism is a false dichotomy resulting from a narrow focus on one or the other of the two legs by which scientific knowledge advances: theory and experiment.

• If religion is the last protoscience, then the corresponding science that is to come could be called security science. 

• The incredible disunity of Protestantism could mean that Protestantism is the laboratory of Christianity.

• The crucial step in going from a protoscience to a science appears not to have been experimentation, but quantification. Examples of early quantifiers were Tycho Brae (astronomy) and Antoine Lavoisier (chemistry). If religion is a protoscience, what would its quantification look like? “Reminder: It’s time to bring up your prayer checklist, tick the boxes that apply under each heading (Adoration, Confession, Thanksgiving, and Supplication), and upload it to the diocesan office. The results of statistical analysis will be announced at Vestry, at which time parishioners may suggest further research questions. This activity parallels and does not replace traditional prayer. All submissions are protected by best-practice data security.”

• The first step in graduating to security science may be compiling a glossary of religious terms and their non-supernatural, parallel interpretations. For example, the Jewish ban on eating pork can be interpreted in this spirit as a measure to prevent trichinosis (a disease transmitted by eating under-cooked pork or wild game). As another example, the four prayer headings enumerated above could be identified in terms of a longitudinal study as control, exposure, favourable outcomes at followup, and adverse outcomes at followup. As a third example, the three persons of the Trinity could map onto the three sources of security science: study of the individual, the society, and the evolutionary history of both (Son, Holy spirit, and Father, respectively).

• Science has to be for everyone.

• We don't have free will in the big things; we have free will in the little things. However, one of the little things can be "planting a seed" that may one day grow into one of those big things and be more to our liking than the big things we see now.

• Should security science take on the task of predicting the unintended consequences of innovations, or is that task so large as to require another new science?

• On the answers to the big questions, the sources of authority are the size of the database and the degree of regulation of the original inquiry. Writing things down would be one rule of inquiry; using a set process would be another; making well-defined measurements would be another; the experiment form would be yet another. The degree-of-regulation parameter takes us smoothly from protoscience to hard science via the qualitative study, which has legitimacy today. The rules of inquiry accumulate over time as the culture learns how to learn. (My post #79 aspires to be at the forefront of this process.)

#74. Protein Batteries and Protein Misfolding Diseases [biochemistry]

CH

Red, theory; black, fact

Disclaimer 

If you are a PD or AD patient or at risk and are seeking a cure outside the medical mainstream, this is not for you. This is written for researchers. 

Inside Alzheimer’s and Parkinson’s 

The commonest protein misfolding disease, Alzheimer disease, features an accumulation of insoluble proteins as amyloid plaques that damage neurons and lead to dementia and death. 

The amyloid precipitates from a solution of amyloid beta protein, which forms by a two-step proteolysis of amyloid precursor protein (APP), an integral membrane protein of neurons.

APP is thought to play a role in the initial stage of synaptic plasticity and contains a copper binding site. 

What is the Power Source Driving Precipitation?

Oxidation of the coordinated copper upon insertion of nascent APP in the plasma membrane could shift the coordination geometry of the copper ion from planar-triangular to pyramidal, with huge changes in the preferred bond angles. If the coordinating protein cannot accommodate these changes without input of activation energy, the result would be a “protein battery”: a protein carrying a metastable “charge” of conformational strain energy. A set mousetrap would be a familiar example of this. 

Role of the Power Source in the Healthy Brain

The local availability of this energy cache may be necessary to allow brief pre- and post-synaptic electrical coincidences to be rapidly captured as preliminary synaptic morphological changes. The calcium-binding site next to the copper binding site (growth factor-like domain) may be the electric field sensor. Coincidence detection would involve same-molecule binding of APP molecules on opposite sides of the synaptic cleft, triggered by propagation of unleashed conformational changes from the copper site into the main extracellular domain, called the heparan-binding domain. (Better known parts of the coincidence detecting system are the NMDA receptor and CAM kinase II).

How the Power Source Goes Wrong

Protein misfolding diseases of the brain may be powered by a short circuiting of the APP energy caches, or analogous caches in proteins subserving other functions. One of those other functions could be replenishing the supply of docked synaptic vesicles in response to a sudden increase in the average neuron firing rate. In that case, the relevant battery protein would be alpha synuclein, which is implicated in Parkinson disease. Local energy caches are also present in humanly engineered electronic circuits, where they are called decoupling capacitors.

Loss of Control of the Stored Energy

 The secretases implicated in Alzheimer disease etiology would serve to degrade the discharged APP molecules. Secretase alpha would act rapidly to clear action-potential-discharged APP that did not make a cross link, and secretase beta would act slowly to clear cross links. Secretase gamma completes the cleavage in both cases. Secretase alpha would have a recognition site for discharged APPs and secretase beta would have an allosteric recognition site for cross links. Secretase beta action releases amyloid beta, the battery part of APP. The stored energy in amyloid beta would drive the polymerization process that leads to amyloid formation. This energy release would involve a conformational change, consistent with the finding that amyloid protein is misfolded. The conformational change could expose hydrophobic residues on the surface of the protein, an energy-requiring step that could lead directly to precipitation due to hydrophobic bonding among the amyloid beta molecules.

This action is easier to imagine for the central hydrophobic domain of alpha synuclein, the immediate effect being not precipitation but pulling two arbitrary ligands on different alpha synuclein molecules into closer proximity for a faster reaction between them. The trigger appears to be phosphorylation of alpha synuclein, not electric field change.

Closing a Fatal Positive Feedback Loop

By mischance, the soluble amyloid beta oligomers that form as intermediates along the amyloid-generating pathway are able to spoof APP cross links, thereby driving ectopic secretase beta activity and closing a feedback loop. This feedback leads to an out-of-control production of amyloid beta that produces Alzheimer disease.

#73. The Self-exciting Small-world Network in Behavioral States and Disease [Neuroscience, Biochemistry]

NE   CH

Red, theory; black, fact

Seen at the Red Roots Trading Co. 

Disclaimer

If you are a cancer patient or at risk and are seeking a cure outside the medical mainstream, this is not for you; this post is written for researchers.

Conventional Thinking on the Nature of Cancer

The refractoriness of cancer (its treatment resistance) is thought by a few authors I read forty years ago to be due to a kind of in-body evolutionary process made possible by the high mutation rate characteristic of these cells. The anticancer drugs we apply to kill the cancer exert an evolutionary selection pressure on the individualistic cancer cells, killing most of them but leaving a residue of accidentally resistant cells that happen to have mutations conferring resistance. These resistant cells then grow back the cancer in a relapse, even harder to kill than before. And so it goes through treatment after treatment until the patient is dead.

But what if that’s wrong?

An Alternative Explanation of Cancer Refractoriness

This seems possible in terms of a “cancer state” that is sustained by re-entrant (circulating) metabolic signaling pathways that form a small-world network (SWN). Curing the cancer requires extinguishing the reentrant activity, but this is difficult because of the robustness of the SWN. If one node in the network is pharmacologically ablated, the signaling can always flow around it by alternative pathways through the network. Thus, robustness becomes refractoriness.

Hub Nodes

The robustness of SWNs depends on their hub nodes—nodes with an unusually large number of connections. The state theory of cancer articulated here therefore directs us to pharmacologically target the hub nodes for greatest therapeutic efficacy. However, a practical therapy also requires selectivity. If we make the leap to assuming that all cellular actions involve entering and leaving states, that all states are identifiable with particular re-entrant SWNs, and that due to the parsimony of evolution, there is much overlap among SWNs and sharing of nodes, it seems possible that the set of hub nodes of a particular SWN can be used as a biochemical address for that SWN, leading to the desired selectivity. The other overlapping SWNs in the treated cell can survive the loss of only one or two hub nodes due to treatment, but not the targeted SWN, which loses all of them.

Research has uncovered amazing complexity inside the eukaryotic cell, and my use of graph theoretical concepts such as SWNs was an attempt to embrace the complexity. I surmised that Nature may have already embraced complexity and that as a result, graph-theoretical constructs will have scientific construct validity in biology.

Problems with the Facts

However, these ideas predict zero response to a single drug, not a large but temporary response. Progress in resolving this will involve consideration of state-trait relationships. For example, a predilection for entering a particular state could be a genetically determined trait, and some states could exist that suppress DNA repair, leading to increasing genetic diversity. Lack of selectivity of anticancer drugs could also be a factor, so that the same drug could delete multiple hub nodes but not all of them.

SWNs in the Brain

Behavioral states such as aggression and siege mentality (the foibles of, respectively, capitalism and communism) also show refractoriness that may have the same cause. In these cases, some likely hub nodes are the neuromodulatory cell groups of the brainstem. An example is the locus ceruleus (LC), which distributes noradrenalin widely in the brain. (Noradrenalin is also the postganglionic transmitter of most of the sympathetic nervous system.) The existence of disciplines such as meditation suggests that some of the SWNs incorporating the LC also incorporate hub nodes in cerebral regions accessible to consciousness, probably including the brain’s language areas. More visceral hub nodes such as blood sugar level are probably also included.

Ancient Foreshadowings of this Theory

The need to treat multiple hub nodes simultaneously to extinguish maladaptive reentrant signaling may have been stated before, but in proto-scientific terms:

“Put on the whole armour of God…”

Saint Paul