Losing my religion

At the end of each year I look back to the preceding year and reflect on how limited my understanding of things nutritional was. A brief moment of self-satisfaction ensues, quickly damped by the realisation that next year will be no different. Each peak climbed reveals higher ranges behind, rolling into the blue medieval distance.

I am fortunate enough to be able to meet with experts in many different life sciences; experts who see far further into the detailed depths of their specialties that I can. They generally use narrow-beam torches which illuminate only a very small part of the huge dark cathedral of elements and linkages that constitute the diet – genome – metabolome – health gestalt. I use a wide-beam torch and try to convince myself that I see a little further afield, but in reality my vision is not better at all. It is vague and lacks focus. 

The complexity of life (gene interactions, reciprocity, multiple messengers, external inputs vs internal echoes, refractions and feedback), the chaos of semi-directional chemistry from which recognisable order somehow emerges, fascinates and appals me. The American writer HP Lovecraft (Poor Howard. Under-appreciated in his day, he lived in a series of diminishing levels of poverty and died early, of an uncommon form of bowel cancer. This disease exactly mirrored his obsession with nameless, underlying malignity.)  had his finger on a seemingly similar pulse when he wrote:

 ‘We live on a placid island of ignorance in the midst of black seas of infinity, and it was not meant that we should voyage far. The sciences, each straining in its own direction, have hitherto harmed us little; but some day the piecing together of dissociated knowledge will open up such terrifying vistas of reality, and of our frightful position therein, that we shall either go mad from the revelation or flee from the deadly light into the peace and safety of a new dark age.’

And the facts continue to accumulate, at dizzying speed. Lately, even the way that facts accumulate has itself been factualized. Heaps’ Law, which builds on Kauffman’s theory of the ‘adjacent possible’ (The adjacent possible is the set of all novel opportunities that open up when a new discovery is made.), successfully predicts the rate at which novel discoveries emerge (1). It explains why discoveries are strongly correlated and often come in clusters; and is a development itself of the theory of punctuated equilibria, which emerged in evolutionary science and has implications far beyond its original field.

But let me take a step back. One way we make intermittent progress is by trying to cram new data into old models to see where they fit – and, more importantly, where they don’t. In this way, models of the human condition have often been superimposed on the technology of the time. 

In the 16^th century, the development of sophisticated clockwork mechanisms and their integration into automata such as the Smithsonian’s wandering monk, originally made for the Holy Roman Emperor Charles 5, paved the way for Descartes‘ concept of humans (and animals) as soft mechanical devices.

The idea of the human as a metaphorical city with headquarters, sewage systems, red light zones etc has similarly been around for centuries. But the city changes over time. Victorian children’s books showed the nerve system as a telegraph system. When I was a child, those illustrations were now telephone systems. By the time I reached my 20’s, these had morphed into embryonic computer systems.

Increasingly, it seems to me, the city model is coming back. But it is a modern city, hyperlinked, overlaid by a dense hum and hubbub of communications, sparkling and comprehensively mutable.

I was taught about separate physiological systems, such as musculo-skeletal, cardiovascular, neurological, endocrinological … But now all these systems are hugely inter-connected, all communicating ceaselessly with each other, merging. Because it turns out that all systems, all tissues and all cells are endocrinological. 

There are the classical hormones such as cortisol, testosterone and thyroxin; but then there are the autocoids, biological factors that act like local hormones, have a brief duration, and mostly act and are metabolized near the site of synthesis. The neurotransmitters fall into this category, as do the currently fashionable and very useful palmitoyl ethanolamide (PEA), nitrous oxide (NO) and possibly brain-derived neurotrophic factor (BDNF); although the experts are divided on that last one.

The cytokines are partly autocoids, but some exert remote effects also; and the exosomes, which I wrote about last week, are different again. 

Exosomes are tiny vesicles that are shed by our cells in response to different stimuli. Some exosomes are profoundly destructive, such as the lysosomal exosomes released in chronic inflammation. These exosomes erode the extra-cellular matrix that holds our cells in the correct orientation, allowing them to communicate, coordinate and function as tissues. The erosion of the matrix is a large part of degenerative disease, and inflammageing.

But exosomes are more diverse than that. They may contain hormones, neurotransmitters, receptors, enzymes, DNA and functional micro RNA called exosomal shuttle RNA (esRNA) (2). In this way they can exert a range of subtle effects near and far from their site of origin, sending information out in waves from every part of the body and responding in turn to incoming information from every part of the body. They change the way in which other cells make proteins, and are changed by them. For example, cells exposed to oxidative stress produce exosomes containing esRNA that tells other, recipient cells to ramp up their antioxidant defences (3).

Our cells talk to each other all the time, and from our perspective that dialogue may be healthy – or unhealthy.

There is communication, for example, in cancer. Cancer cells, like all cells, have something like a drive to live. Killing off large numbers of cancer cells simply makes the surviving cells more ‘determined’ to grow. This occurs via DNA damage, apoptosis, caspase-3 and the subsequent synthesis of prostaglandin E₂ (PGE₂), a potent growth factor that can enhance growth of surviving cancer cells and thus lead to accelerated tumor repopulation. This is known as the Phoenix Rising effect, and it may be possible to neutralise this rake in the grass using either indomethacin (4) or fish soup (5).

It not that the centre cannot hold. Rather, there is no centre, no stasis, no insularity. No man, and no cell is an island. This is super-string theory transmuted into biology and if you think you understand it, you haven’t understood it at all. I certainly don’t. It tugs at me …. and it gets worse.

Exosomes are present in foods such as milk, and they too contain functional, non-digestible RNA, which is probably absorbed into our blood streams when we consume these foods (6). The food-based esRNA probably then codes for non-human proteins in our cells, making us subtly more like what we eat. 

Exosomes are in saliva too (7), and probably in seminal fluid. So when we drink milk, or when we kiss and have sex – do we fall under someone else’s genetic influence? And if so, what kind of influence? Do we adapt to them in some way? Do we become closer? Do we become less likely, perhaps, to respond to them as foreign? Are these exosomes actually emissaries? 

I believe that the 19^th century Western philosophy of individualism, in whose evening rays we still bathe, has hindered us from seeing how deeply and profoundly inter-connected we actually are. At a conference last year in Singapore, a Franco-Japanese microbiologist told me that the gut feelings we sometimes have about others may be our microbiome picking up, and responding to, volatiles produced by the other person’s microbiome; and then relaying this information to us via the gut/brain axis. His evidence was preliminary, and I look forward to reading his work in published form later this year.

Not only are the spaces between us becoming less absolute than we were taught a century ago, but so are the spaces within us. A recent USA-China collaboration showed that information can jump across fissures cut surgically through the brain, by means of electrical fields (8). This opens the possibility that our thoughts and emotions may be influenced by external, as well as internal electromagnetic fields; such as the localised geomagnetic anomalies (9) which some have linked to the ancient oracular sites. The theory of quantum brain dynamics, developed by scientists such as Prof. Hans Chaudhry of the New Jersey Institute of Technology, holds that consciousness itself is an electromagnetic field. What does this mean for mobile phones? 5G?

In fits and starts, therefore, emerging evidence is forming a new paradigm where we live in fragments no more.

All our cells and tissues modulate each other in many and often unexpected ways. For example, exercising the leg muscles sends messages to the brain that boost the formation of stem cells in the sub-ventricular region. Stop walking, and the numbers of stem cells fall by 70% (10). This is bad news, because the sub-ventricular zone is where almost all new brain cells are formed.

A sedentary lifestyle therefore makes it difficult for the body to produce the new brain cells needed to handle stress and adapt to challenge in our lives. 

In short, there is a vast multi-directional informational traffic and there is huge redundancy; a fuzzy and quasi-democratic logic so complex that the system as a whole is not dependent on any one sub-system or input. Changes in any one of these sub-systems is subsumed into the elastic and reflexive whole, allowing the whole (us) to be rapidly and almost infinitely responsive to a bewilderingly diverse and changing environment, while remaining, somehow, ourselves.

This is a little like the aerodynamic instability built into fighter planes that makes them more agile; but it is a deeper and more complex form of instability that creates the unlikely amalgam of adaptability and constancy that enables the human experience.

From this perspective, we also need to re-calibrate our thinking about the non-communicable diseases. They are conceptually unlike the diseases that sprang from Robert Koch’s beautiful 19^th century work, whose postulates still inform the medical profession’s ideas about disease to this day. In reality they are not diseases at all, but syndromes.

Given that the non-communicable diseases have multiple genetic and environmental risk factors, there are clearly many routes that can lead eventually to what appears to be, in clinical terms, the same degenerative condition.

Alzheimer’s appears to come in at least 4 or 5 sub-types, with differing pathoaetiologies (11). Once you have met one person with Parkinson’s you have met one person with Parkinson’s (For this I am indebted to Simon Stott, who produces an erudite and highly informative blog at www.scienceofparkinsons.com); the disease is extremely variable, and one sub-type – SWEDD – doesn’t destroy the dopaminergic neurones that we used to think integral to the condition. Atheroma can form due to errors and imbalances in many metabolic and physiological paths, as can arthritis, osteoporosis, and so on.

These are not diseases in the Koch’s Postulates sense at all. We label them diseases because of administrative convenience and inertial thinking, but these are merely final common clinical pathways that emerge from many different starting points. No wonder the pharmaceutical approach is so patchy!

We are in a dark room, groping at the tail, trunk or toenails of the elephant. Perhaps all we can hope to achieve is a little understanding of the fine details of a small part of the picture.

But there are a few general signals we can see emerging from the noise.

Most cases of premature (ie avoidable) death are related to dysnutrition.  Chronic inflammation caused by our unbalanced diet and lifestyle contributes to accelerated ageing and the complexity of dying. There are many ways to die, and as many as 13 different kinds of cell death.

I will come back to this in a future post.

Let me end with a nod to the ‘A Scientific Dissent from Darwinism’ list, which passed the 1,000 mark this month. This list, which is only open to those with a PhD in a natural science, now stands at 1034 signees, among whom you will find eminent academics from a range of prestigious institutions. They say, carefully, that they are “.. skeptical of claims for the ability of random mutation and natural selection to account for the complexity of life. Careful examination of the evidence for Darwinian theory should be encouraged.”

Even though I was raised on Darwinism, a mode of thinking that has borne rich fruit in many seemingly unrelated fields from economics to AI to cosmology, I cannot disagree with that last statement. The existence of horizontal gene transfer (12), which occurs mostly in single cell organisms, is enough to make one reconsider the prevailing evolutionary models; and it is another reminder of the inter-connectivity of all life.

The emerging incredible complexity of life and death suggests that a new type of Darwinism may need to evolve.

REFERENCES

1. Iacopo Iacopini et al. Network Dynamics of Innovation Processes, Physical Review Letters (2018). DOI: 10.1103/PhysRevLett.120.048301
2. Batagov AO, Kurochkin IV. Exosomes secreted by human cells transport largely mRNA fragments that are enriched in the 3′-untranslated regions.

 Biol Direct. 2013 Jun 7;8:12. 

3. Eldh M, Ekström K, Valadi H, Sjöstrand M, Olsson B, Jernås M, Lötvall J. Exosomes communicate protective messages during oxidative stress; possible role of exosomal shuttle RNA. PLoS One. 2010 Dec 17;5(12):e15353. 
4. Allen CP, Tinganelli W, Sharma N,  Nie J, Sicard C, Natale F, King M, Keysar SB, Jimeno A, Furusawa Y, Okayasu R, Fujimori A, Durante M, Nickoloff J. DNA Damage Response Proteins and Oxygen Modulate Prostaglandin E₂ Growth Factor Release in Response to Low and High LET Ionizing Radiation. Front Oncol. 2015; 5: 260. 
5. Espe M, Holen, He J, Provan F, Chen L, Øysæd KB,  Seliussen J. Hydrolysed

              fish proteins reduced activation of caspase-3 in H₂O₂ induced  oxidative                stressed liver cells isolated from Atlantic salmon (Salmo salar).  Springerplus. 2015; 4: 658.

6. Izumi H, Tsuda M, Sato Y, Kosaka N, Ochiya T, Iwamoto H, Namba K, Takeda Y. Bovine milk exosomes contain microRNA and mRNA and are taken up by human macrophages. J Dairy Sci. 2015 May;98(5):2920-33. 
7. Lässer C, Alikhani VS, Ekström K, Eldh M, Paredes PT, Bossios A, Sjöstrand M, Gabrielsson S, Lötvall J, Valadi H. Human saliva, plasma and breast milk exosomes contain RNA: uptake by macrophages. J Transl Med. 2011 Jan 14;9:9. 
8. Chiang CC, Shivacharan RS, Wei X, Gonzalez-Reyes LE, Durand DM. Slow periodic activity in the longitudinal hippocampal slice can self-propagate non-synaptically by a mechanism consistent with ephaptic coupling. J Physiol. 2019 Jan;597(1):249-269. doi: 10.1113/JP276904. 
9. Rabeyron T, Loose T. Anomalous Experiences, Trauma, and Symbolization Processes at the Frontiers between Psychoanalysis and Cognitive Neurosciences. Front Psychol. 2015; 6: 1926.
10. Adami R, Pagano J, Colombo M, Platonova N, Recchia D, Chiaramonte R, Bottinelli R, Canepari M, Bottai D. Reduction of Movement in Neurological Diseases: Effects on Neural Stem Cells Characteristics. Frontiers in Neuroscience, 2018; 12 DOI: 10.3389/fnins.2018.00336
11. Bredesen DE. Metabolic profiling distinguishes three subtypes of Alzheimer’s disease. Aging (Albany NY). 2015 Aug;7(8):595-600.