Cancer Is Not Caused By Mutations

This quote is from... 1974 but yet most people rather "believe" in bullshit than understand the complexity and complex systems. 

We find ourselves at the present time in the era of molecular biology, and we are perhaps unduly influenced by the genetic code as the dominant principle in biology. Perhaps, in a decade or two from now, the dominant principle may shift to another plane, which in turn will influence our speculations about tumor causation.

- Biochemist Isaac Berenblum, 1974

Once again, I am learning all this after Max...

Similarly, instead of simply targeting the cancer, altering the microenvironment to disfavor its proliferation may provide a more viable long-term strategy, as the former immediately selects for resistance, accounting for the difficulty in keeping a patient in remission. Highlighting the importance of the microenvironment in regulating development, homeostasis, and cancer, biologist Mina Bissell writes,

“The sequence of our genes are like the keys on the piano; it is the context that makes the music.”

Cancer depends on context, as should our approach to treatment.

Of particular interest is the discrepancy between cancer frequencies at different sites. For example, colorectal cancer is very common while small intestinal cancer is 100 times less common despite the fact that the small intestine is five times longer (30 feet versus 6 feet for the colon) and characterized by nearly identical rates of mutation as the colon. The microenvironments are strikingly different, however, with the colon being host to more diverse and numerous microbiota. In addition, colorectal cancer almost exclusively occurs in the distal colon rather than the proximal colon where fermentation is greatest and short-chain fatty acid (SCFA) concentrations are typically higher. Lack of sufficient dietary resistant starch may prevent production of a short-chain fatty acid called butyrate, which lowers colonic pH, prevents pathogen invasion, and appears to preclude carcinogenesis, lending further evidence to the role of the colonic ecosystem in preventing or promoting cancer. To further illustrate the importance of the tissue microenvironment, Bissell expounds,

“Indeed, how else would one explain the tissue specificity of heritable cancers, for example, BRCA1 and breast cancer, where, despite mutations in all of more than 10 trillion cells, the tumors are not only tissue specific but also formed from just one or a few cells of those tissues?”

 

Representational Drift In The Brain

Ever fascinating Ed Young on how little we know about the jelly inside our skulls: 

But other scientists have shown that the same phenomenon, called representational drift, occurs in a variety of brain regions besides the piriform cortex. Its existence is clear; everything else is a mystery. Schoonover and Fink told me that they don’t know why it happens, what it means, how the brain copes, or how much of the brain behaves in this way. How can animals possibly make any lasting sense of the world if their neural responses to that world are constantly in flux? If such flux is common, “there must be mechanisms in the brain that are undiscovered and even unimagined that allow it to keep up,” Schoonover said. “Scientists are meant to know what’s going on, but in this particular case, we are deeply confused. We expect it to take many years to iron out.”

[---]

The team showed that if a neuron in the piriform cortex reacts to a specific smell, the odds that it will still do so after a month are just one in 15. At any one time, the same number of neurons fires in response to each odor, but the identity of those neurons changes. Daily sniffs can slow the speed of that drift, but they don’t eliminate it. Nor, bizarrely, does learning: If the mice associated a smell with a mild electric shock, the neurons representing that scent would still completely change even though the mice continued to avoid it. “The prevailing notion in the field has been that neuronal responses in sensory areas are stable over time,” says Yaniv Ziv, a neurobiologist at the Weizmann Institute of Science who was not involved in the new study. “This shows that’s not the case.”

“There have been hints of this for at least 15 years,” across many parts of the brain, Schoonover told me. The hippocampus, for example, helps animals navigate their surroundings. It contains place cells — neurons that selectively fire when their owner enters specific locations. Walk from your bed to your front door, and different place cells will fire. But these preferences aren’t fixed: Ziv and others have now shown that the locations to which these cells are tuned can also drift over time.

[---]

It might be less common in other sensory hubs, such as the visual cortex, which processes information from the eyes. The neurons that respond to the smell of grass might change from month to month, but the ones that respond to the sight of grass seem to mostly stay the same. That might be because the visual cortex is highly organized. Adjacent groups of neurons tend to represent adjacent parts of the visual space in front of us, and this orderly mapping could constrain neural responses from drifting too far. But that might be true only for simple visual stimuli, such as lines or bars. Even in the visual cortex, Ziv found evidence of representational drift when mice watched the same movies over many days.

“We have a hunch that this should be the rule rather than the exception,” Schoonover said. “The onus now becomes finding the places where it doesn’t happen.” And in places where it does happen, “it’s the three F’s,” Fink added. “How fast does it go? How far does it get? And … how bad is it?”

[---]

Schoonover and Fink compare the discovery of representational drift with the work of the astronomer Vera Rubin. In the 1970s, Rubin and her colleague Kent Ford noticed that some galaxies were spinning in unexpected ways that seemed to violate Newton’s laws of motion. Her analysis of that data provided the first direct evidence for dark matter, which makes up most of the matter in the universe, but has never been observed. Similarly, drift indicates “that there’s something else going on under the hood, and we don’t know what that is yet,” Schoonover said.

But the comparison between drift and Rubin’s spinning galaxies fails in one important way. Rubin knew that she was onto something odd because she could compare her data against Newtonian mechanics — a solid and thoroughly described theory of physics. No such theory exists in neuroscience. The field has a very clear idea of how individual neurons work, but it gets much fuzzier when it comes to neuronal networks, entire brains, or the behavior of whole animals.

[---]

“There’s a real hunger in the field for new ideas,” Fink told me, which is why, he thinks, he and Schoonover haven’t yet faced the kind of vicious pushback that scientists with dogma-busting data tend to encounter. “People are really desperate for theories. The field is so immature conceptually that we’re still at the point of collecting factlets, and we’re not really in a position to rule anything out.” Neuroscience’s own representations of the brain still have plenty of room to drift.

Tranquility Tricks From Keanu Reeves!

Sometime around my 30's, I started following these simple tricks. 

1. Don't argue with people who don't listen. 

2. Listen more, talk less. 

3. This is the most important thing which had profound change in my life - Rating the open-mindedness of the other person: 

There are many writers I’ve stopped reading in the last few months. Their level of open-mindedness just isn’t there. They believe they are right based on their own experience, and to question them is an act of war. So, I simply mute their voice and move on to more open-minded voices.

Open-mindedness is sexiness — not because it makes your biceps appear bigger — but because open-mindedness is the gateway to understanding the world we live in.

- Read the whole piece here

This means avoiding some of the "famous" columnists, journalists, authors (past and present), some books, completing avoid news and sometimes avoiding an entire discipline such as "study" of consciousness. 

It is much easier to remove things/habits we have in life rather than adding new ones to bring tranquility. 

Drone Pilot Doug Thron - Rescues Animals After Natural Disasters

- Watch the full documentary here

And interview with Doug Thron (thank you, sir!) here: 

What was your first big rescue using a drone?

My first big rescue using a drone was in the Bahamas after Hurricane Dorian. I was there helping to deliver aid and film the destruction when I spotted a dog roaming around the mountains of debris. He obviously hadn’t had any water or much food for days. He was really apprehensive at first, but warmed up over the course of the day, as I just sat with him. Dog food and water helped! The next day, some animal rescuers came with me to get him. He’s such an incredible dog, and meant so much to me, so I adopted him and named him Duke after a sign I’d seen where I found him.

[---]

What is it like when you spot an animal in an area of devastation where there is no other sign of life? 

It’s great to be able to rescue these animals so much more efficiently and faster and, in many cases, find animals that never would have been found.  It’s different everywhere I go—finding animals when there aren’t any others alive nearby is always really hard. But in places like Louisiana, where I was searching in so many neighborhoods, it gives you a feeling of hope when you find a cat or dog, knowing it was someone's pet. 

In other places, like Australia, I’d be covering dozens of miles a night, sometimes and only finding an occasional animal. It’s really sad because you realize how many thousands of animals didn’t make it. It’s also really hard to see how fires and other natural disasters as a result of climate change are taking out the last patches of unentered habitat and endangered animals.

How heart-wrenching can it be?

It can be really heart-wrenching to find animals that are severely wounded, but it’s wonderful to be able to save them. 

How euphoric is it when you make a great save?

It’s awesome to be able to save people's cats and dogs because frequently, that might be the only thing they have left after a fire or hurricane. Obviously, for the animal's sake, it’s so incredible because without the infrared drone, in many cases, the animal would have never been found and would have died, sometimes a slow and painful death.

What is your drone like?

The Matrice 210 V2 are the drones I use with an infrared camera, spotlight, and 180x zoom lens. The combination of using those three attachments for animal rescue has never been done before.

How much time do you spend doing animal rescue work? What else do you do?

The rescue work is pretty continuous for 9 to 10 months during the fire and hurricane seasons. After that, there are occasional lost pets to be found.

 

 

What A Question!

"Only OK if I say something objective and stoical: Ian remarking that a time might come when I’d have to let go: Carol asking about Rebecca’s wedding “Are you afraid you won’t see England again?” Also, ordinary expressions like “expiration date”… will I outlive my Amex? My driver’s license? People say— I’m in town on Friday: will you be around? WHAT A QUESTION!

- Christopher Hitchens, Morality 

Ever since I read Hitchens last book (and what a book it was) in 2012; I knew time would come when I would ask a similar question with Max. And I did in 2015. 

Max had benign Melanoma scare in 2015 and the week after surgery when the Vet told us nothing to worry about, I asked for refill of his ear cleaning liquid. The vet's office had only the largest size bottle and gave that for Max. The date on the bottle was 08/13/2015. The first thought that came to mind was will Max outlive before this bottle goes empty. 

On 12/20/2019 Max passed away and the bottle was still not empty. Neo, Fluffy and Garph started using it and eventually, on 06/01/2021 - almost seven years later, it's now empty. 

Embracing the stoic exercise of Memento Mori years ago has been one of the best things in my life. 

To quote Hitches again on how body dissipates slowly in front of our eyes:

It’s normally agreed that the question ‘How are you?’ doesn’t put you on your oath to give a full or honest answer. So when asked these days, I tend to say something cryptic like, ‘A bit early to say.’ (If it’s the wonderful staff at my oncology clinic who inquire, I sometimes go so far as to respond, ‘I seem to have cancer today.’) Nobody wants to be told about the countless minor horrors and humiliations that become facts of ‘life’ when your body turns from being a friend to being a foe: the boring switch from chronic constipation to its sudden dramatic opposite; the equally nasty double cross of feeling acute hunger while fearing even the scent of food; the absolute misery of gut-wringing nausea on an utterly empty stomach; or the pathetic discovery that hair loss extends to the disappearance of the follicles in your nostrils, and thus to the childish and irritating phenomenon of a permanently runny nose. Sorry, but you did ask… It’s no fun to appreciate to the full the truth of the materialist proposition that I don’t have a body, I am a body.

In hindsight, now with little more knowledge on how cancer works and metastasis being an oxymoron - I should have taken Max's 2015 benign melanoma extremely seriously. Cancer and metastatic doesn't care about our "benign" classification. 

I bought a new bottle of ear cleaning liquid for Neo which is half the size of the bottle Max used. The question now is will I outlive that bottle?

On Drinking

Moments after Max passed away, I made a promise to him that I will never drink. It's not that I was an alcoholic but since I had decided to keep on breathing without Max, I forced myself to better use that time without Max for rest of my time consciously. This was something I learned from Richard Feynman and later from the George E. Vaillant's brilliant book Triumphs of Experience: The Men of the Harvard Grant Study, chapter 9 is titled alcoholism:

• Where alcohol is concerned, it is what people do, not what they say, that is important.
• 57 percent of the Grant Study divorces were associated with alcoholism. 

I have observed numerous times losing myself and becoming an other entity with little or no self control even with a glass or two of wine. I didn't like who I was in those moments. So, I have been thinking about quitting for a long time, check out my 2013 post.  To be clear, I do drink beer still but never touched other alcohol nor do I miss it. 

Kate Julian has a brilliant column titled America has a drinking problem. I would say not just Americans but the world has a drinking problem. 

Evolutionary theory behind sapiens' love of drinking (and maybe reason why Microsoft makes bad software): 

Natural selection has endowed humans with the ability to drink most other mammals under the table. Many species have enzymes that break alcohol down and allow the body to excrete it, avoiding death by poisoning. But about 10 million years ago, a genetic mutation left our ancestors with a souped-up enzyme that increased alcohol metabolism 40-fold.

This mutation occurred around the time that a major climate disruption transformed the landscape of eastern Africa, eventually leading to widespread extinction. In the intervening scramble for food, the leading theory goes, our predecessors resorted to eating fermented fruit off the rain-forest floor. Those animals that liked the smell and taste of alcohol, and were good at metabolizing it, were rewarded with calories. In the evolutionary hunger games, the drunk apes beat the sober ones.

But even presuming that this story of natural selection is right, it doesn’t explain why, 10 million years later, I like wine so much. “It should puzzle us more than it does,” Edward Slingerland writes in his wide-ranging and provocative new book, Drunk: How We Sipped, Danced, and Stumbled Our Way to Civilization, “that one of the greatest foci of human ingenuity and concentrated effort over the past millennia has been the problem of how to get drunk.” The damage done by alcohol is profound: impaired cognition and motor skills, belligerence, injury, and vulnerability to all sorts of predation in the short run; damaged livers and brains, dysfunction, addiction, and early death as years of heavy drinking pile up. As the importance of alcohol as a caloric stopgap diminished, why didn’t evolution eventually lead us away from drinking—say, by favoring genotypes associated with hating alcohol’s taste? That it didn’t suggests that alcohol’s harms were, over the long haul, outweighed by some serious advantages.

[---]

At a talk he later gave on wu-wei at Google, Slingerland made much the same point about intoxication. During the Q&A, someone in the audience told him about the Ballmer Peak—the notion, named after the former Microsoft CEO Steve Ballmer, that alcohol can affect programming ability. Drink a certain amount, and it gets better. Drink too much, and it goes to hell. Some programmers have been rumored to hook themselves up to alcohol-filled IV drips in hopes of hovering at the curve’s apex for an extended time.

His hosts later took him over to the “whiskey room,” a lounge with a foosball table and what Slingerland described to me as “a blow-your-mind collection of single-malt Scotches.” The lounge was there, they said, to provide liquid inspiration to coders who had hit a creative wall. Engineers could pour themselves a Scotch, sink into a beanbag chair, and chat with whoever else happened to be around. They said doing so helped them to get mentally unstuck, to collaborate, to notice new connections. At that moment, something clicked for Slingerland too: “I started to think, Alcohol is really this very useful cultural tool.” Both its social lubrications and its creativity-enhancing aspects might play real roles in human society, he mused, and might possibly have been involved in its formation.

He belatedly realized how much the arrival of a pub a few years earlier on the UBC campus had transformed his professional life. “We started meeting there on Fridays, on our way home,” he told me. “Psychologists, economists, archaeologists—we had nothing in common—shooting the shit over some beers.” The drinks provided just enough disinhibition to get conversation flowing. A fascinating set of exchanges about religion unfolded. Without them, Slingerland doubts that he would have begun exploring religion’s evolutionary functions, much less have written Drunk.

[---]

For the past 25 years, archaeologists have been working to uncover the ruins of Göbekli Tepe, a temple in eastern Turkey. It dates to about 10,000 B.C.—making it about twice as old as Stonehenge. It is made of enormous slabs of rock that would have required hundreds of people to haul from a nearby quarry. As far as archaeologists can tell, no one lived there. No one farmed there. What people did there was party. “The remains of what appear to be brewing vats, combined with images of festivals and dancing, suggest that people were gathering in groups, fermenting grain or grapes,” Slingerland writes, “and then getting truly hammered.”

Over the decades, scientists have proposed many theories as to why we still drink alcohol, despite its harms and despite millions of years having passed since our ancestors’ drunken scavenging. Some suggest that it must have had some interim purpose it’s since outlived. (For example, maybe it was safer to drink than untreated water—fermentation kills pathogens.) Slingerland questions most of these explanations. Boiling water is simpler than making beer, for instance.

Göbekli Tepe—and other archaeological finds indicating very early alcohol use—gets us closer to a satisfying explanation. The site’s architecture lets us visualize, vividly, the magnetic role that alcohol might have played for prehistoric peoples. As Slingerland imagines it, the promise of food and drink would have lured hunter-gatherers from all directions, in numbers great enough to move gigantic pillars. Once built, both the temple and the revels it was home to would have lent organizers authority, and participants a sense of community. “Periodic alcohol-fueled feasts,” he writes, “served as a kind of ‘glue’ holding together the culture that created Göbekli Tepe.”

Things were likely more complicated than that. Coercion, not just inebriated cooperation, probably played a part in the construction of early architectural sites, and in the maintenance of order in early societies. Still, cohesion would have been essential, and this is the core of Slingerland’s argument: Bonding is necessary to human society, and alcohol has been an essential means of our bonding. Compare us with our competitive, fractious chimpanzee cousins. Placing hundreds of unrelated chimps in close quarters for several hours would result in “blood and dismembered body parts,” Slingerland notes—not a party with dancing, and definitely not collaborative stone-lugging. Human civilization requires “individual and collective creativity, intensive cooperation, a tolerance for strangers and crowds, and a degree of openness and trust that is entirely unmatched among our closest primate relatives.” It requires us not only to put up with one another, but to become allies and friends.

As to how alcohol assists with that process, Slingerland focuses mostly on its suppression of prefrontal-cortex activity, and how resulting disinhibition may allow us to reach a more playful, trusting, childlike state. Other important social benefits may derive from endorphins, which have a key role in social bonding. Like many things that bring humans together—laughter, dancing, singing, storytelling, sex, religious rituals—drinking triggers their release. Slingerland observes a virtuous circle here: Alcohol doesn’t merely unleash a flood of endorphins that promote bonding; by reducing our inhibitions, it nudges us to do other things that trigger endorphins and bonding.

Over time, groups that drank together would have cohered and flourished, dominating smaller groups—much like the ones that prayed together. Moments of slightly buzzed creativity and subsequent innovation might have given them further advantage still. In the end, the theory goes, the drunk tribes beat the sober ones.

But this rosy story about how alcohol made more friendships and advanced civilization comes with two enormous asterisks: All of that was before the advent of liquor, and before humans started regularly drinking alone.

Now going back to me still drinking beer; there tons of low alcohol beers and even zero alcohol beers.  I have just ordered non alcoholic bourbon.  Innovation is not just happening in tech world. There are a small group of passionate people working on non-tech products as well. 

If you are baffled and ask what is the point of non-alcoholic beer or bourbon? Then its about time you learn to use self-deception as an ally. Kudos Robert Trivers!

Miyabeacin - Found In The Balk Of The Willow Tree Has Potential In Cancer Therapy

Abstract

Willow (Salix spp.) is well known as a source of medicinal compounds, the most famous being salicin, the progenitor of aspirin. Here we describe the isolation, structure determination, and anti-cancer activity of a cyclodimeric salicinoid (miyabeacin) from S. miyabeana and S. dasyclados. We also show that the capability to produce such dimers is a heritable trait and how variation in structures of natural miyabeacin analogues is derived via cross-over Diels-Alder reactions from pools of ortho-quinol precursors. These transient ortho-quinols have a role in the, as yet uncharacterised, biosynthetic pathways around salicortin, the major salicinoid of many willow genotypes.

- Full paper here

Butts - An Evolutionary Marvel

To peer into the soul of a sea cucumber, don’t look to its face; it doesn’t have one. Gently turn that blobby body around, and gaze deep into its marvelous, multifunctional anus.

The sea cucumber's posterior is so much more than an exit hole for digestive waste. It is also a makeshift mouth that gobbles up bits of algae; a faux lung, latticed with tubes that exchange gas with the surrounding water; and a weapon that, in the presence of danger, can launch a sticky, stringy web of internal organs to entangle predators. It can even, on occasion, be a home for shimmering pearlfish, which wriggle inside the bum when it billows open to breathe. It would not be inaccurate to describe a sea cucumber as an extraordinary anus that just so happens to have a body around it. As Rebecca Helm, a jellyfish biologist at the University of North Carolina at Asheville, told me, “It is just a really great butt.”

But the sea cucumber’s anus does not receive the recognition it deserves. “The moment you say ‘anus,’ you can hear a pin drop in the room,” Helm said. Bodily taboos have turned anuses across the tree of life into cultural underdogs, and scientific ones too: Not many researchers vocally count themselves among the world’s anus enthusiasts, which, according to the proud few, creates a bit of a blind spot—one that keeps us from understanding a fundamental aspect of our own biology.

The appearance of the anus was momentous in animal evolution, turning a one-hole digestive sac into an open-ended tunnel. Creatures with an anus could physically segregate the acts of eating and defecating, reducing the risk of sullying a snack with scat; they no longer had to finish processing one meal before ingesting another, allowing their tubelike body to harvest more energy and balloon in size. Nowadays, anuses take many forms. Several animals, such as the sea cucumber, have morphed their out-hole into a Swiss Army knife of versatility; others thought that gastrointestinal back doors were so nice, they sprouted them at least twice. “There’s been a lot of evolutionary freedom to play around with that part of the body plan,” Armita Manafzadeh, a vertebrate morphology expert at Brown University, told me.

But anuses are also shrouded in scientific intrigue, and a fair bit of squabbling. Researchers still hotly debate how and when exactly the anus first arose, and the number of times the orifice was acquired or lost across different species. To tap into our origins, we’ll need to take a squarer look at our ends.

- More Here