Cancer and holobionts: is there a link?

 

Image from Vyshenska et al, 2017

I have been studying the work on cancer of the Italian researcher Stefano Fais. You can find a recent review of his work at this link. Basically, Fais sees tumor cells as the result of an unbalanced metabolism that leads these cells to develop on their own, even using anoxic processes to grow. He maintains that it is possible to slow down the development of these cells by making their metabolic growth processes more difficult, in particular using proton pumps to make their local environment more basic. 

I am not expert enough to be able to give an informed judgement on these ideas. But, as you may imagine, it led me to consider if there were a link between cancer and the concept of holobionts and, yes, there is a line of research in this area. Several researchers seem to be exploring the idea that cancer is the result of a "dysbiosis," that is an unbalance of the host's microbiota. For instance, in a 2014 work by Apidianakis, we can read:

".... the host genetic background and that of the microbiome, define the intestinal hologenome, which is influenced by age and the environment toward homeostasis or disease. Thus, the intestinal disease may ensue when the intestinal hologenome is imbalanced, that is, when a genetically predisposed or old host interacts with its dysbiotic microbiota in an inadequate or harmful dietary or lifestyle-shaped environment."

The problem, here, is that there is no link whatsoever with Fais's idea that tumors are related to acidity. Maybe there is a link, somewhere, but the story is horribly complicated and I leave it here. It is just a note that you may find interesting and perhaps worth studying in depth.

Genes, Demes, and Holobionts: What genetic studies tell us of the behavior of our ancestors

 

 Once you discover the concept of "holobiont," its ramifications keep surprising you. Here is a brief discussion of how the competition among the human meta-holobionts called demes affected and was affected by the human sexual behavior. 

How could it be that for a few thousand years only one human male out of about 20 females left descendants? What had happened that had removed so many males from the human gene pool? This is a story that would require an entire book to explain, but it is so fascinating that I thought I could write a quick survey, here. 

So, take a look at the image above. It is taken from a 2015 article by Karmin et al.  There is a lot of information in that figure, but let's concentrate on the left graph. It shows the degree of diversification of the human Y-chromosome over time. You know that the Y-chromosome is something that only males have in humans, so the curve is roughly proportional to the active male reproducing population. The more diversified it is, the more males there are around, reproducing. Be careful: this is not the total male population. It is the population of those males who reproduce. Males who never mate with a fertile female don't appear in the graph. Note also that females are tracked using their mitochondrial DNA that they inherit from their mothers.

As you can see, the population of reproducing males is always smaller than that of the females (right graph). That doesn't mean that the total number of males (reproducing + non-reproducing) is smaller than that of the females -- for all we know, these numbers have remained comparable over human history. It seems that human males always have more competition and more troubles to reproduce than females (if you are male, you understand what I mean). So a sizable number of males always disappear from the genetic history of the species, even though they did exist and maybe they were also sexually active. It is just that they left no descendants.

But the impressive feature of the male curve above is the dip that takes place between 7,000 to 5,000 years ago. Hard times for males: only about one reproducing males out of 20 reproducing females. Ouch! (or maybe not so much of an ouch for those who did reproduce, who had 20 females each). That's weird: how can that be?

As always, we should take into account that all scientific results are affected by uncertainty. But this work seems to be solid and so far it has not been challenged. So, the question is, what happened that made our female ancestors so selective in choosing just one male in 20 as the father of their children? 

You bet that a lot of hypothesis have been proposed to explain this catastrophe that hit human males in their reproductive success (but, again, it doesn't mean they didn't have female partners, just that they didn't mate with them when they were fertile). But what happened? An epidemics? The wrath of God? The spread of the fashion of monastic life? 

It is a long, long story and we are far from having understood this pattern. But I think that a 2018 paper by Zeng et al. gave the correct interpretation. It all has to do with demes.

One more paragraph, one more thing to learn: what the chuck is a "deme"? Well, it is a known concept in biology, although not so common for most of us. Basically, a deme is a relatively stable group of individuals who often mate within the group and rarely outside. In human terms, you may think of a deme as the equivalent of a "tribe" or a "clan." 

A characteristic of human demes is that they are often patrilinear: that is, they are dominated by a male hierarchy: there is a patriarch on top, his son, grandsons, and maybe great-grandsons. The females are more mobile. They practice exogamy, that is they tend to marry outside the deme (clan). The exchange of females among tribal groups is well known in anthropology. 

Now, you see here the holobiont emerging: a deme is a kind of a holobiont, we might call it a "meta-holobiont" in comparison to the normal human holobiont. But a holobiont is a holobiont is a holobiont. It is a group of organisms that collaborate in a symbiotic structure. Not just that, but demes practice "holobiont sex" by exchanging genetic material in the form of female organisms. See how many patterns tend to repeat? Wonderful!

Here goes the explanation by Zeng et al., that I think makes a lot of sense. As all holobionts, demes have a finite lifetime. They can die because of various natural reasons, starvation, disease, etc. Or they may be killed by aggressive neighborhood demes. And here is the trick. In a deme, there is very little differentiation in the Y-Chromosomes. The males are all related to each other and you know that brothers all have the same Y-Chromosome. So, the deme dies, the Y-chromosome dies. How sad! Those males who were part of that deme don't pass their Y-Chromosome to their descendants, so they disappear from the human genetic history. But so is the way things are. The great holobiont called Gaia loves life, but She knows that there cannot be life without death.

But the death of a deme doesn't mean the disappearance of the female genetic imprint. Not at all. Since females practice exogamy, likely, the females of a dead deme had sisters in other demes that survived. Besides, killing a deme in war doesn't mean that the winners exterminate all the females, not at all and for good reasons! Males consider the females as a war prize. Nowadays we tend to think that killing males and raping their females is not a very nice behavior, but it was very common in history (and still is). 

And here goes the final trick that explains the whole story. The drop in the reproducing male number takes place in a period of great expansion of the human population. It means that the demes were closer to each other and fighting for increasing scarce resources. It meant holobiont-style selection. Those demes that were less efficient in exploiting the available resources, and also less effective in war, disappeared, and with them a lot of Y-chromosome lineage. And that's what you see in the curve. Amazing!

But then, what happened that restored the chance of reproducing for human males? Well, there came the age of kingdoms, and then the age of empires, and kings and emperors don't like clans to fight against each other. They want all the males to fight for them, and that changed everything. Another long story that I'll tell in another post. But all these stories that deal with holobionts are fascinating! 

And here is how Conan the Barbarian interprets deme competition

 

Longevity secrets of a 100-year old holobiont

 

These four holobionts are related by vertical gene transmission through their female organisms. Among other things, their mitochondria have all the same DNA. The oldest of the three, Liliana, is 100 year old. There follow Grazia (68), Donata (31) and Aurora (1). Photo taken in July 2020

When my mother-in-law, Liliana, turned 100 last month, several people asked me what is the secret of her longevity. Not only it is not usual to reach that age, but to reach it in relatively good conditions. Liliana surely has problems: she walks very slowly and she tends to forget things. But her mind still works and, the day of her birthday, she categorically refused to be carried to the garden where we were having the celebration. She insisted to walk there by her own, even climbing the steps of the stairs leading there. It took her a lot of time, but she made it.

As you know, there is an entire field of research that studies centenarians. In particular, the gut microbiota of centenarians seem to age together with the main organism, but we don't know exactly how longevity is related to these modifications. So, here I'll just tell you something about Liliana and you may make your own deductions on what may be the ways to reach a very old age, still healthy.

First of all, Liliana was born in 1920 and she was young in a world that was very different from ours. The kind of diet, the way of living, the ways of seeing the world -- she might as well have been born on another planet. Imagine a world where there is no central heating, no TV, no telephone, where women still washed clothes by hand and hung them to dry out of the windows. A world without showers, only bathtubs where the water had to be heated by a wood fire. In the morning, there were standalone washbasins in the bedrooms where you could wash your face when you woke up. In winter, it was not uncommon to find that the water had frozen solid in the basin. 

It was a world where cars were rare and reserved for the rich: life was mainly within the area that could be reached on foot. And when a boy wanted to woo a girl, he would normally use a method already described by Boccaccio in his "Decameron" (14th century), that is making "passes" on foot under the windows of his beloved. Liliana confirmed to me that this was the way her future husband courted her, in the late 1930s. 

Coming of age in Italy during the 1930s meant a very different kind of life for women. Liliana never learned to drive a car and she can't even ride a bicycle. She completed he middle school curriculum ("scuola media" in Italian), but even for a middle-class girl, as she was, it would have been considered a little weird to continue her studies. She was supposed to become a housewife, and she did: she never had a salaried job during all of her life, although she worked occasionally as a seamstress. But her life was far from being easy. She went through the ordeal of WW2 when she survived the bombings and the shelling of Florence. Her boyfriend was drafted in the Italian army and he barely survived the war in North Africa, then he was wounded in the Italian civil war in 1944. The war may have been a watershed for many people alive today: those who survived it were especially resilient people. 

So, Liliana had an eventful life. One reason was her decision to marry a Sicilian man, something that was considered a scandal in his family. In the 1940s it was like, say, if today a middle-class American girl were to decide to marry a poor boy from Afghanistan. For Liliana, that implied several adventures but she was stubborn. She wanted that boy and she had it. Eventually she settled with her husband in the house that her grandfather had bought for the whole family in Florence and where she is still living today. She had three children, all born at home. Right now, she has four grand-children and two great-grand children.

As you can imagine from what I just told you, Liliana could be, and still is, a rather stubborn character. But I can also say that she is not very aggressive, she has always been flexible and friendly to everybody. A positive character in many ways, I have never seen her truly angry or mad at someone. Maybe this easygoing character was a help for her in getting old so gracefully. 

How about Liliana's diet? I can tell you that if you want to have some idea of what Liliana eats today, you can find it in books such as  "A Room with a View" (1908) by E.M. Forster and "Etruscan Places" (1932) by D.H. Lawrence. Incredible as it may sound, there was a time when the British would complain about Italian cuisine: the tasteless soups, the hard-to-chew boiled meat, the uninspiring kind of cheese made from sheep milk, and the mysterious castagnaccio that, according to Forster, tasted "partly of the paper in which it was wrapped, partly of hair oil, partly of the great unknown." And I have a feeling that Forster really wanted to write "the great unwashed." 

Today, Liliana still eats those thin soups that Lawrence hated and that nobody would want anymore in Florence. She eats cheese, eggs, and a little meat, not much but she is not vegetarian. She likes cooked vegetables, she seems to be a little wary of raw greens and she never cultivated anything edible in her garden -- she was a housewife, not a peasant. She is not fond of pizza, but occasionally she eats it. She never went to a Chinese restaurant in her life, she knows what a "hamburger" is (she can make them at home) but she has no idea of what a McDonald's restaurant might look like. She doesn't drink wine and she has never tasted beer in all her life. One characteristic that may be relevant to her longevity is how she tends to eat slowly. And she never-ever was overweight.

Then, how about Liliana's microbiota? We have no analysis of it, but I can tell you that she had flatworms in her gut for a long time. Some people say that flatworms are part of our biome and that they are good for health. On this point, I can't say much, but surely flatworms didn't harm Liliana. Then, I can also tell you that she never took a shower in her life and she never washed her hair with soap. On this, she seems to have been extremely modern, following the advice we are receiving today from James Hamblin in his recent book "Clean." Hamblin has not been taking showers for 5 years, not much in comparison to Liliana who has been shower-less for much longer. In both cases, anyway, the effect on preserving one's skin's microbiota seems to have been good. At 100, Liliana still has thick, white hair. 

What else? Liliana told me that once she took a bath in the sea. She didn't like it and she never wanted to repeat the experience. She hated the sunshine and she would never dream of sunbathing. She never took an airplane flight, her longest trip ever was from Florence to Sicily, for her honeymoon. It was just after the war and the trip took two days by an old, chugging steam train.

Among other things, Liliana always maintained a deep distrust in medical doctors and in medicines. For most of her life she succeeded in not seeing doctors and avoiding pills of any kind. Now, of course, she needs various pills everyday, but not so many. Ah... and of course she never smoke cigarettes nor indulged in any kind of what we call today "recreational drugs." She did like coffee, though, although she can't drink it anymore.

So, where is Liliana's secret of longevity? Hard to say. Maybe we could conclude that it consists in not taking too many showers, eating a little of everything, and slowly. Maybe eating thin soups helps, just as having survived a major world war. And a little coffee won't harm you. But maybe the main point is to stand by one's ideas but also take life as it comes. We are all holobionts, just passengers of the ecosystem of this planet that's engaged in an immense journey that has been ongoing for billions of years. And onward we go, fellow holobionts!

The Virome: Viruses are an essential part of the human holobiont

 

Image Source

 

 

 

Eradicating viruses and bacteria may not be so easy as some people think. We are surrounded by viruses, we eat viruses, we drink viruses, we breathe viruses. And the "virome" is an essential part of the human holobiont.

From "Half-Earth" by E. O. Wilson (p. 125).

 

"Although recognized only in 1988, Prochlorococcus are far from rare. They are in fact the most abundant organism in tropical and subtropical seas around the world. They live in waters as deep as two hundred meters and reach local densities of more than a hundred thousand per millimeter. Because the tiny cells account for 20 to 40 percent of the biomass of all photosynthetic organisms present between 40 N and 40 S in the open ocean, they are responsible for up to half the local net primary production.

 

Yet, if Prochlorococcus along with a second superabundant bacterium, Pelagibacter, are the most important organisms, might they be the prey of viruses that are even smaller? Experts used to think that such micro-predators are at best relatively rare. In 2013, however, new methods in the fast-moving field of ultramicroscopic research revealed the presence of viruses on an averaged of billions per liter of seawater, all are bacteriophages (literally, eaters of bacteria), of which one HTVC010P is the most abundant... it must be classified as the most abundant known species on Earth.

But what is a "superorganism," in the end?

What is a superorganism, exactly?

I was mulling over this question and I came up with the classic example: the ant colony is supposed to be a superorganism in the sense that all the organisms in it share the same genome, just like in a human beings all cells have the same DNA (except mitochondria, of course).

But no, wait! That cannot be: ants are sisters, not clones. They may even have different fathers. For a quirk of the genetic setup of male ants, ant sisters share 75% of their genes, not 50% as human siblings do. But they are not clones. So an ant colony is not a superorganism, but a kind of tightly knit holobiont.

But then, a discovery: that's not true, either! As reported in this paper, there are ant colonies where all the ants are clones of each other! Unbelievably, some ants have discover tricks to completely eliminate the need of males: yes, no males and no queens. They reproduce by parthenogenesis. These colonies are true superorganisms, not holobionts. And I keep discovering new things: one that starts to be very common is that males seem to be obnoxious and useless in all species!

The Earth Goddess According to Jenny Jinya

The Earth Goddess in the interpretation of Jenny Jinya

Jenny Jinya is a phenomenal German artist who knows something about empathy, the fundamental element that keeps together the multiform creatures we call "holobionts."

For a taste of her awesome work, you may start from this one. (be careful, this is powerful stuff -- it may make you cry like a child).

In the most recent comic strip by Jenny Jinya, we even see appearing the Goddess of life herself, mistress of all the holobionts of Earth. You can find it here. Enjoy the good ending!