Are we breeding for stupid dogs?

 "Little brainiacs and big dummies: Are we selecting for stupid, stout, or small dogs?"

Intriguing study. The title is catchy, so I read it. 

A general scaling quotient related to brain size, or encephalization, for all mammals is defined as the amount of brain mass exceeding that related to an animal's total body mass. Brain size non-linearly scales with body weight between species within mammals to around the 0.67 power. However, within species, this scaling exponent appears to be much smaller. An early study compares dogs with non-canid species. According to this study, we are breeding dogs to have smaller brains. 

Dogs today have smaller relative brain size than dogs 100 years ago. That may not be an intention, but we do selectively breed them for certain behavioral traits as well as well as physical appearance. The famous Russian Silver Fox experiment confirms that (6 generations of breeding and choosing individuals for tameness resulted in a domestic fox). Keep in mind that genes linked to behavior and physical appearances may be linked to brain size. 

This encephalization quotient generally estimates 'evolved intelligence' or other behavioral traits, "under the assumption that the bigger the brain per kilogram of bodyweight beyond what would be required for basic neural functions, the greater the intelligence." But have we humans also bred for lower brain function? aka 'stupid' dogs?

My interest was more in how this compares to non-dog canids than within domestic dogs. A phenomenal earlier study* (1986) compared brain size and weight between all families within the carnivore order (all carnivore families, genera and most species). The study also used metrics including ecology and behavior as well as body and brain size, developing an encephalitic quotient (EQ) range. Canids placed in between the families Ursidae (bear family) and felids (cats). 

What is interesting is the EQ within domestic dogs compared to the within species of non-dog EQ. The current study found that EQ decreases with increasing body weight in dogs: "Small dogs had higher EQ than their non-dog canid counterparts of comparable size, but large dogs had lower EQ than similarly sized non-dog canids."

Encephalization quotient decreases with increasing body weight in dogs. The dashed black line represents the regression line for dogs, the dark gray solid line represents the regression line for dogs from the Richet dataset, and the light gray solid line represents the regression line for canids from the Gittleman dataset. The regression line for canids crosses the regression lines for dogs at approximately 10–15 kg.

In other words, domestic dogs have a brain-size-to-body-size relationship that markedly differs from the general rule between-species relationship (power function of 0.26 rather than 0.65–0.67). That's quite a difference. 

But this is even more impressive: modern dogs have lower relative brain sizes than dogs of a century ago. There are two possible biological explanations. First, humans purposely select for smaller heads, which includes the size of the cranium. This is unlikely. 

The second and more likely explanation is that modern dogs are fatter than their lighter counterparts from a century ago: "...plentiful evidence exists that dogs, like people, in the United States are experiencing an increasing prevalence of obesity." 

Authors in the recent study recognize an important methodological criteria related to the above explanation: "Researchers a century ago recognized the importance of examining brain-size-to-body-size relationships in animals that are in 'optimal condition,' and cautioned including data for domestic animals that often differ in body condition from their wild counterparts." Definitely true. Regardless, the prevalence of obesity in dogs (and humans) is concerning. 

What about intelligence? Are bigger dogs smarter than small dogs due to brain size, or vice versa?

Despite common beliefs we all hear, the authors conclude "no behavioral evidence exists that small breed dogs are more intelligent than large breed dogs." Most of us know that behavioral studies are fraught with discrepancies in methodology and interpretation. Additionally, several studies failed to observe a relationship between brain size and cognition. Some studies have reported that certain breeds are more "trainable" or perform better at certain skills. Similar reports are associated with horse breeds.

The authors offer a more plausible explanation; what these studies and anecdotal claims more correctly identify is a "selection of specific morphotypes for specific tasks, and certain cognitive skills that underpin those tasks, rather than selecting for or against overall intelligence." Specific physical attributes are more suited for specific tasks and skills than others, and behavior is a result of genes and learning. 

"Such a hypothesis finds support in studies that identify “trainability” with working breeds vs. non-working breeds, rather than size. Given that working breeds are generally larger than non-working breeds, size might simply be a poor surrogate for “working breed.”

I enjoy good challenges (and controversies) in biology. They force people to critically think (and they should). The authors in this study challenge existing and generalized assumptions about interpretations and conclusions relating to differences in body sizes with a subtle hint of well-deserved sarcasm. 

"This observation flies in the face of assigning an encephalization quotient to dogs—in our study, small breed dogs had a relative brain size far exceeding their “expected” brain size, while large and giant breed dogs had relative brain sizes of mental midgets. Therefore, applying an encephalization quotient to dog breeds appears nonsensical, and challenges the entire anthropocentric notion of encephalization as a measure of intelligence."

This, to me, is the coup d'état challenge for scientists that arrive at assumptions and generalizations that persist on shaky evidence. It also represents a challenge to those that choose and pick their data or facts to support their preconceived assumptions. In this case, the challenge is how we perceive intelligence in dogs, and perhaps all animals. Including our own genus, Homo spp.**

Read the last two paragraphs of the paper where the authors discuss "What makes a dog a dog?" and how selecting for smallness has a limit (which it does, so stop it). 

"....regardless of how small domestic dogs become, brain size must be conserved to accommodate sufficient neuronal complexity for the dog to maintain its “dogness.”

In all, excellent discussion and writing for a published scientific paper.  

* Gittleman J.L. Carnivore brain size, behavioral ecology, and phylogeny. J. Mammal. 1986;67:23–36.

** A recent article (sometime in March 2021) challenged our modern assumptions about the inferior intelligence, or lack of, in Neandertals and Denisovans. You'll have to do a google search for that article. 

Oh, Phosphorus. How art thou?

I'm bored with spinning, TV and reading my books. It's cold and raining outside. So I'm reading a few papers on how phosphates evolved to facilitate biological life. Physics, chemistry and information theory. 

The word phosphorus derives from the Greek phōsphoros: phōs ‘light’ + -phoros ‘-bringing’. Perhaps the Greeks knew more than we do.

I asked this question of my graduate biochemistry instructor: "How did phosphorus evolve to be the key element of life?". She just shook her head and answered, "You just have to sometimes accept that we don't have the answers, that we just don't know."

"Nah. I bet we do, or will soon."

That was in the mid-1980's. Westheimer published a paper, "Why nature chose phosphates", in 1987 proposing a theory (partly) answering my question. His theory was refined in 2013 by Kamerlin, et al: "Why nature really chose phosphates." Then, Liu et al took it to a different level with "How Prebiotic Chemistry and Early Life Chose Phosphate". 

Goldford, et al. commented in the introduction of their paper ("Remnants of an Ancient Metabolism without Phosphate," 2017), "Phosphate is essential for all living systems, serving as a building block of genetic and metabolic machinery. However, it is unclear how phosphate could have assumed these central roles on primordial Earth, given its poor geochemical accessibility." But we now know how phosphates assumed that essential role. 

Hess et al published earlier this year (Nature,16 March 2021) another theory,
"Lightning strikes as a major facilitator of prebiotic phosphorus reduction on early Earth". (Remember the Greeks?) It circles back to biophysicist Werner Loewenstein's 1999 book ("Touchstone of Life") in which he explains why lightening probably facilitated phosphorus being the first and basic element for life on Earth (and may be on other planets). This book is enlightening for integrating information theory, physics, chemistry, and molecular biology. (One star of the book is Maxwell's demon.)

But, wait! A treatise explores the 'phosphorus enigma' at the largest scale: the book, "The Chemical Evolution of Phosphorus: An Interdisciplinary Approach to Astrobiology" (Enrique Maci -Barber, PhD, Professor of Condensed Matter Physics in Madrid, Spain). In the forward of the book, Sun Kwok (astronomer studying the physics and chemistry of stellar evolution) wrote:

"This book beautifully traces the stellar origin of the element phosphorous, its chemical properties, and the observations of phosphorous-based molecules and minerals in the interstellar medium and in the solar system. [The author] then connects the astronomical studies with the role of phosphorous played in living organisms, presenting the biochemistry of biomolecules that incorporate phosphorous, and the roles that these molecules play in the origin of life on Earth."

Unfortunately, the book is also a hefty $150; far out of my price range. 

Branching off but parallel to the road of physics and chemistry, information theory has expanded understanding of prebiotic and current life. My first introduction into this was more like an epiphany while reading Loewenstein's book when it appeared on the shelves in 1999. It filled in the gaps for a continuing passion of concepts in cell signaling. It wasn't just about chemistry; physics was the parent. (College physics, taught only as mechanical physics, turned me off to the subject. I endearing called  it "'fysics; the other 'f' word". Despite that my father, a biophysicist/biochemist, tried to convince me to not ignore 'fysics'.)

Realistically, information theory integrates physics, chemistry, molecular biology, structural biology, geology, and more. It's like a spider web with life (and death) at its core. Whenever anyone, especially during this pandemic, mentions the spike protein and ACE2 receptor, antibodies and ligand, and, especially, the immune system, my immediate response is "Conformation is everything", a mantra I picked up  in biochemistry and incessantly repeat. (Network theory, inclusive of information theory, is now being applied to the immune system.)

Dr. Chris Adami, theoretical physicist and computational biologist, is the one of the few researchers using information theory to understand the physical and medical sciences and evolution. Life should not be thought in terms of chemical events. Instead, it should be thought of as information transmission. Adami comments during an interview:

"Information is the currency of life. One definition of information is the ability to make predictions with a likelihood better than chance. That’s what any living organism needs to be able to do, because if you can do that, you’re surviving at a higher rate... Think of evolution as a process where information is flowing from the environment into the genome. The genome learns more about the environment, and with this information, the genome can make predictions about the state of the environment."

When asked about the origin of life, he relates one of a few hypotheses amongst scientists for the circumstances of life origins: 

"I have heard tremendous amounts of interesting stuff about what happens in volcanic vents [under the ocean]. It seems that this kind of environment is set up to get information for free. It’s always a question in the origins of life, what came first, metabolism or replication. In this case it seems you’re getting metabolism for free. Replication needs energy; you can’t do it without energy. Where does energy come from if you don’t have metabolism? It turns out that at these vents, you get metabolism for free."

 However, nothing is free. Maxwell Demon knows that. The prime denomination of that currency of information is energy. And one of the earliest components of life that transfers energy is a phosphate group in an energy unit: adenosine triphosphate (ATP). With the origin of ATP began the synthesis of large biomolecules. The release of a phosphate group supplies energy for molecular couplings, resulting in adenosine diphosphate (ADP). Subsequent combinations release a phosphate group that reattaches to ADP, forming ATP. This is a positive feedback loop that cycles over and over. 

First there was lightening. Over millions of years of trial and error a system became more stable, and it also became more adaptive. And then life was born.

We have come closer to understanding the origins of life. And I am closer to understanding how and why phosphorus evolved as the key element of life. Did Nature choose this, or did this choose Nature as it's product? That may be an ouroboros question. 

(A comment by Adami echoes thoughts throughout my higher education and academic years: "...the more you learn about different fields, the more you realize these fields aren’t separated by the boundaries people have put upon them, but in fact share enormous commonalities."  Yes.)

Molecular Demons and Gedankenexperiments

 What caffeine does to the brain. 

This question has popped up in short ‘vacant spaces’ (periods of quiet without other junk thoughts) the past few months with all these various virus variants (couldn’t resist the redundancy) popping up. This morning I saw this Twitter thread echoing the same questions. 

Then I had a Gedankenexperiment, a thought experiment. It appeared to me that if we can determine the molecular configuration of these virus variants, we should also be able to computationally predict those with high probability of becoming thermodynamically stable or increased fitness. This is used in predicting ligand docking (protein conformational fit with target protein, aka ‘ligand’) for drug development. 

We could then do automatic searches in newly submitted virus variant genome sequences for such candidates. Why else would one mutation and consequent conformation change in the spike protein be independently popping everywhere? Because it is a top thermodynamically fit conformation. And given the vast uncontrolled landscape in which the virus can ‘choose’ a random mutational configuration that increases transmission offers evidence that the virus is winning within a relatively short time. Especially when TWO adventitious mutations come together.  (See Twitter screenshots below)

It’s the Molecular Demons in information theory. 

Now back to mundane life.

Bats and viruses co-evolved!

Bats harbor many viruses and are a source of old and new emergent viral diseases in humans. Why? 

Two papers review the unique bat immunology summarize what we know thus far, as well as some as yet untested theories. In short, a bats' immune system is competent at confusing and tricking virus biology, and we don't quite fully understand all of it. 

Given their herculean immune system, viruses have to 'work hard' to fool and evade their immune system to actually cause disease, without, of course, killing them. (A virus that kills its host quickly is a dead end for a virus. It may be able to replicate a few times, but it can't transmit all those new virions to other hosts after it dies. So, dead end.)

One way for viruses to test the the bat immunity barriers is a random process of mutations and evolving behavior of the virus to successfully infect and replicate (fitness). I'll explain some of that in another post (information theory). One of those barriers is heat: viruses don't like heat. One immunity mechanism of mammals to fight virus infection is a fever. It may not kill all viruses, but it slows their biological trajectory to infect cells and replicate. Another component of that is it buys time for the rest of the immune system to respond and bring in the artilleries: antibodies, T-cells, etc. They attach to and disable or kill virus particles, and destroy already infected cells so that the little new virions inside the cells die, too. 

This was one of two approaches I used to rid very important plants (nuclear stock) of viruses before they went to certified nurseries for mass propagation and sale to industry growers and commercial nurseries (1980's-1990's). The approach was to expose a plant to high heat in a growth chamber, the hottest temperature it could stand, then take 1mm size pieces of the apical meristem (growing point) and grow them on tissue culture media containing an anti-viral, now known as Ribavirin. (Protocol developed by me and collaborator at university in CA.)

So now that I have established some credible evidence for the relationship of heat and viruses, albeit in plants, keep that in mind in this next part. 

Five scientists from US, UK and AUS methodically detailed over five pages a hypothesis of why bats and viruses co-evolved together(1). It actually makes sense, although not good for other mammals, especially humans. 

I recall from reading a review last year that viruses must be super-evolvers, aka go through many and numerous random mutations, in order to successfully infect and evade the bat immune system. By the time some of those viruses jump from bat to another animal, especially another mammal, they are super-duper viruses and often deadly to humans. 

Think about the first SARS-1 virus pandemic: a short-lived pandemic because it was less transmissible than the current SARS-2, but it was also more deadly. Short-lived because countries quickly contained and eliminated it. Also consider MERS, another bat coronavirus that emerged after SARS-1. Very deadly, and very poorly transmissible. It, too, was quickly controlled. That it was a deadly virus contributed to that. 

A decade later a new SARS-like virus emerges: it's highly transmissible, not as deadly, but it spreads like wildfire. It has, however, been able to also evade part of our immune system if the latter is in any way compromised, including obesity, diabetes, etc. Two other important factors helping it along is the relatively poor and/or belated human response in controlling spread, and its stealth: it can infect mammals, replicate and transmit to others while not inducing any or many symptoms. A caveat to the latter is we now know that some infected people of all ages may have had little to no symptoms but still developed some tissue damage (e.g. cardio myelitis, kidney, etc) that occurred slowly enough not to elicit recognizable symptoms. l can see this as a stealthy way to evade the bat immune system, too. 

Back to co-evolution of bats and viruses. This is a good summary from their abstract: 

 "We hypothesize that flight, a factor common to all bats but to no other mammals, provides an intensive selective force for coexistence with viral parasites through a daily cycle that elevates metabolism and body temperature analogous to the febrile response in other mammals. On an evolutionary scale, this host–virus interaction might have resulted in the large diversity of zoonotic viruses in bats, possibly through bat viruses adapting to be more tolerant of the fever response and less virulent to their natural hosts."

And, 

" We hypothesize that the increased metabolism and higher body temperatures of bats during flight might serve as an evolutionary adjuvant to their immune systems, providing a powerful selective force against virulence and promoting the diversity of viruses that infect bat populations. Perhaps counter-intuitively, this would enable bats to tolerate a greater diversity of viruses that have a high potential for virulence when transmitted to other mammals.

The hypothesis also might help explain why co-evolved bat viruses cause high pathogenicity when they spill over into other mammals because the bat-derived viruses might survive well under both febrile and cooler conditions."

Pretty respectable! Actually, it's brilliant. Don't blame the bats, or their viruses. It's just another biological ecosystem that we are not meant to get involved in. So leave the bats and their habitats alone. Many of those viruses become zoonotic because we tend to invade their habitats. 

Isn't science beautiful? 😁

1. Bat Flight and Zoonotic Viruses, O’Shea, et. al. Emerging Infectious Diseases, Vol. 20, No. 5, May 2014.

Further reading on bat immunology:

Novel Insights Into Immune Systems of Bats, A. Banerje, et. al. Frontiers in Immunology, Vol. 11, No. 26, January 24, 2020.

The bat-virus detente, R. Ehrenberg, Knowable Magazine, June 19, 2020.